bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–10–04
63 papers selected by
Cédric Chaveroux, CNRS
  1. Substrate Binding Relieves Autoinhibition of the Mammalian GCN2 Kinase.
  2. Conformational diversity of collided ribosomes determines stress signaling.
  3. Epitranscriptomic regulation of Notch signaling.
  4. Impact of the Diversity in the 5' UTR on Translation Regulation.
  5. NAT10 governs development through the Xrp1-mediated stress response rather than its RNA acetylation activity.
  6. A DRACH Observed/Expected Metric Reveals the Evolutionary Landscape of Epitranscriptomic Regulation Across Bilateria.
  7. Changes in the translational landscape during red clover necrotic mosaic virus infection.
  8. Regulation of cellular proteostasis via mitochondrial protein import.
  9. Fluorescent proteins misreport ribosome abundance under translation inhibition.
  10. Translation fidelity mechanisms and their changes in aging.
  11. A small molecule increases mycobacterial translation fidelity without a fitness cost by targeting ribosomal protein S5.
  12. A conserved archaeal protein with evolutionary links to bacterial ribosome hibernation and eukaryotic energy sensing.
  13. EZH2 Inhibition Induces a Metabolic Stress Response Sensitizing Triple-Negative Breast Cancer to Glutaminase Targeting.
  14. Post-translational acylation of proteins in colorectal cancer.
  15. Tracking cellular biomolecular condensate dynamics under proteostatic stress with middle-down phosphoproteomics.
  16. ATF3: Friend or foe in cellular stress and repair? A context-dependent stress rheostat framework.
  17. N6-methyladenosine promotes temozolomide resistance through mRNA stabilization in glioblastoma cells.
  18. From Translation Milestones to Clinical Breakthroughs: Decision-Making Hubs and Translational Strategies for RNA-Binding Proteins in the Immunotherapy of Haematological Malignancies.
  19. Site-specific inhibition of translation initiation via 2'-O-methylation.
  20. Adaptation to heat stress by diversification of the vertebrate heat shock transcription factor family.
  21. METTL3 Increases Temozolomide Resistance in MGMT-Negative Glioblastoma by Enhancing CBX5 mRNA Stability in an m6A-IGF2BP2-Dependent Manner.
  22. PABPC1 in Cancer: From a Translational Housekeeper to a Stress-Responsive Regulatory Hub.
  23. Polyphenism Through RNA Chemical Modifications.
  24. Disruption of RNA metabolism and its impact on protein homeostasis.
  25. mRNA processing in cancer immunotherapy: emerging targets, resistance mechanisms, and therapeutic opportunities.
  26. Sex-specific metabolic regulation by the Drosophila RNA-binding protein Nab2.
  27. Mechanistic Role of eIF4E in the Hallmarks of Cancer: A Translational Control Perspective.
  28. GDF15 as a sentinel of metabolic integrity: a narrative review of stress signaling, multisystem pathophysiology, and therapeutic potential.
  29. Collided ribosomes are rescued by the endonuclease Rae1 and trans- translation.
  30. METTL3-m6A-mediated downregulation of IGFBP6 accelerates atherosclerotic plaque formation through GPX4-induced ferroptosis.
  31. Mitohormesis linking metabolic dysfunction and neurodegeneration: implications for dementia and therapeutic strategies.
  32. Integrated stress response activation in combination PG3 and cisplatin-treated TP53 -mutated head and neck squamous carcinoma cells induces potent apoptotic response.
  33. Recoding by N1-methylpseudouridine guides rational mRNA vaccine design.
  34. RNA-Protein Assemblies: A Review of Biophysical Principles and Coarse-Grained Modeling Approaches.
  35. Unlocking the Potential of Yeast Protein for Functional Foods: A Multiscale Overview of Bioactivity, Processing, and Application Challenges.
  36. Regulation of ER Stress-Associated Gene Expression by Lifeguard in Human Breast Cancer Cells.
  37. Integrative Nanopore and Illumina sequencing reveals age-associated tRNA modification and CCA-tail dynamics in yeast.
  38. Endoplasmic reticulum stress as a mechanistic link between nutrition and inflammatory bowel disease.
  39. IGF2BP1-Mediated m6A Modification Enhances the Stability of circ_0088302 to Promote Gastric Cancer Progression.
  40. METTL14-mediated m6A modification of CXCL9 mRNA regulates macrophage CS polarization to suppress OSCC growth and stemness.
  41. Kinetic Control of Nuclear-encoded Mitochondrial mRNA Localization and Local Translation.
  42. Full-length transcriptomics and proteomics reveal how genome minimization reshapes gene expression in synthetic bacteria.
  43. Biphasic SMN condensates safeguard stress-induced cytoplasmic mislocalization of splicing RNPs.
  44. Pumilio and Brain tumor regulate the expression of Smaug during the Drosophila maternal-to-zygotic transition.
  45. Posttranslational Modifications of p62/SQSTM1 in Health and Disease.
  46. [Inhibition of RBM5 expression by the interaction between hsa_circ_0006200 and EIF4A3 and its impact on cervical cancer progression].
  47. Toward Mapping Spatiotemporally Resolved Transcriptomes and RNA-Protein Interactions.
  48. Integrated multi-PTM omics reveals key host pathways in human coronavirus 229E infection.
  49. Cell-free RNA fragmentomics: rethinking the biology of RNA liquid biopsies.
  50. Post-translational modification crosstalk in acute pancreatitis: linking acinar stress to innate immune amplification and tissue repair.
  51. RBP-Driven RNA sorting and local translation establish the molecular identities of individual sensory axons.
  52. Mechanisms of Plant Responses to Waterlogging-Induced Hypoxia: Integrated Regulatory Reprogramming for Survival and Recovery.
  53. Protein rheostasis: quality control in metastable proteomes.
  54. Intronic RNA of yeast RPL22 paralogs acts as an allosteric switch.
  55. Ubiquitin-Dependent Protein Quality Control in Polyglutamine Diseases.
  56. Endothelial Proteotoxic Stress Drives Inhaled Benzene-Induced Vascular Inflammation in Mice.
  57. FBXL21 regulates diurnal proteostasis in skeletal muscle by targeting DNAJB6 and client proteins.
  58. The mitochondrial DNA-cGAS-STING axis in colorectal cancer: a focused review of context-dependent roles and therapeutic opportunities.
  59. JP-1302 inhibits RNA polymerase I transcription and induces nucleolar stress in cancer cell lines.
  60. Dynamic tRNA modification programs align codon usage with growth-phase-specific gene expression in Pseudomonas aeruginosa.
  61. Pharmacological translation of cancer missense mutations for therapeutic targeting with small molecules.
  62. Thermosensor OsTT3.1 enhances rice thermotolerance by degrading OsGSK2 to reduce OsHsfB2c phosphorylation and nuclear translocation.
  63. Ebola virus mRNAs contain RNA structures that are critical for viral infection and targetable by antisense oligonucleotides.
  1. bioRxiv. 2026 Sep 13. pii: 2026.09.09.750423. [Epub ahead of print]
    Substrate Binding Relieves Autoinhibition of the Mammalian GCN2 Kinase.
    Marco A Catipovic, Rachel Green.
      Cells respond to amino acid starvation and translational stress through the integrated stress response (ISR) kinase GCN2. Current models maintain that GCN2 senses these stresses either by binding deacylated tRNAs that accumulate during amino acid starvation or by recognizing ribosome collisions that arise from perturbation of translation elongation. As tRNA charging is inherently coupled to translation elongation, assessing the relative contributions of these two pathways has proven difficult. To fully separate the roles of these potential agonists, we reconstituted the regulation of GCN2 in vitro using recombinant proteins. GCN2 has low basal activity, which is stimulated by the addition of ribosomes or the ribosomal P-stalk. By contrast, deacylated tRNAs fail to activate GCN2 both in vitro and in vivo and instead counteract activation by the ribosome and inhibit GCN2 auto- and substrate phosphorylation. This inhibition of autophosphorylation requires the presence of GCN2's substrate, eIF2α, suggesting that the substrate plays a role in kinase regulation. Indeed, eIF2α binding to a newly defined autoinhibitory loop in the GCN2 kinase domain relieves its repression and stimulates autophosphorylation of the kinase's activation loop. Together, these data redefine the role of tRNAs in the regulation of GCN2 and reveal a mechanism novel to kinases in general by which substrate binding regulates activation loop phosphorylation.
    DOI:  https://doi.org/10.64898/2026.09.09.750423
  2. bioRxiv. 2026 Sep 10. pii: 2026.06.16.730951. [Epub ahead of print]
    Conformational diversity of collided ribosomes determines stress signaling.
    Jeffrey J Li, Timo Denk, Matthias Thoms, Allen R Buskirk, Roland Beckmann, Rachel Green.
      Ribosome collisions trigger pathways that clear stalled ribosomes, and when sufficiently abundant, the integrated stress response (ISR) through GCN2 and the ribotoxic stress response (RSR) through ZAK. The inhibitors anisomycin (ANS), emetine (EME), and didemnin B (DDB) are commonly used to induce collisions in studying these responses. Here, we demonstrate that these drugs induce distinct signatures: ANS and DDB potently activate ZAK whereas EME does not. We define transcriptional programs induced by these inhibitors, where collisions induce the RSR and general inhibition of translation leads to an RSR-independent response. Surprisingly, we find that collisions induced by EME, unlike ANS, are not cleared by ASCC3. The cryo-EM structure of human disomes stalled by EME reveals its mechanism of inhibition and a conformation distinct from ANS-stalled disomes. These differences in collision geometry explain the different outcomes in quality control and signaling activation, showing how ribosome stalling events can yield distinct cellular responses.
    DOI:  https://doi.org/10.64898/2026.06.16.730951
  3. Cell Signal. 2026 Sep 26. pii: S0898-6568(26)00573-5. [Epub ahead of print]149 112914
    Epitranscriptomic regulation of Notch signaling.
    Vahid Saqagandomabadi, Sahar Sarrafzadeh Zargar, Matin Pooladi, Ehsan Pashay Ahi.
      Notch signaling is extensively controlled post-transcriptionally, yet the contribution of RNA chemical modifications has only recently begun to be resolved mechanistically. Here, we review epitranscriptomic regulation of Notch signaling, focusing on RNA modification-dependent control of the processing, localization, stability, translation, and editing of Notch-related transcripts. To distinguish direct transcript-level regulation from global pathway effects, we propose a four-step mechanistic framework requiring site-resolved modification mapping, modifier- or reader-dependent alteration of RNA fate, a corresponding change in Notch signaling output, and transcript-specific rescue or epistasis. Applying this framework further highlights reader identity as a key determinant of m6A directionality: YTHDF2-mediated recognition can promote transcript decay, whereas YTHDF1 and IGF2BP-family readers can enhance translation or transcript stability and thereby reinforce Notch signaling. Across developmental, stem-cell, cancer, neurobiological, and immune contexts, these mechanisms can tune both the intensity and persistence of Notch signaling. Because the available evidence remains strongly dominated by m6A, other RNA marks are discussed more cautiously. This transcript-centered framework separates direct epitranscriptomic regulation of Notch components from broader pathway rewiring and provides a basis for prioritizing mechanistically supported RNA-level therapeutic targets.
    Keywords:  Cancer; Epitranscriptomics; Notch signaling; Post-transcriptional regulation; RNA modifications; RNA stability; Stem cells; Translational control
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112914
  4. Wiley Interdiscip Rev RNA. 2026 Sep-Oct;17(5):17(5): e70060
    Impact of the Diversity in the 5' UTR on Translation Regulation.
    Giulia Cardamone, Melanie Flohr, Irina Bode, Tobias Schmid.
      The 5' untranslated region (UTR) of mRNAs is crucial to regulate translation initiation. Diversity in the 5' UTR can be created by alternative transcription start site (TSS) selection and alternative splicing. Alternative TSS directly impact the first exon length or alternative first exon usage, while alternative splicing further contributes to generating different 5' UTR isoforms by for example, cassette exons inclusion, intron retention, and alternative 5' or 3' splice sites. Alternative TSS and alternative splicing in the 5' UTR directly affect translation efficiency by generating different isoforms that may include or exclude regulatory sequence elements and secondary structures in the 5' UTR. Among the regulatory elements, 5' UTRs may harbor translation-inhibitory upstream open reading frames (uORFs) as well as internal ribosome entry sites (IRESs), which are able to recruit the ribosome in a cap-independent manner. Both uORF- and IRES-mediated mechanisms contribute to target-specific protein production, especially under stress conditions associated with an inhibition of global translation. Mechanisms generating different 5' UTR isoforms therefore represent an additional sophisticated layer to regulate transcript-selective translation efficiency.
    DOI:  https://doi.org/10.1002/wrna.70060
  5. Sci Adv. 2026 Oct 02. 12(40): eaeg0399
    NAT10 governs development through the Xrp1-mediated stress response rather than its RNA acetylation activity.
    Lin Wang, Zhao Xue, Shuyang Gao, Yanhua Wang, Houguang Lu, Bo Peng, Tianyi Fan, Ying Cao, Jian-Quan Ni, Guoliang Lu, Jinzhong Lin, Dong Yan.
      N4-acetylcytidine (ac4C) is installed by N-acetyltransferase 10 (NAT10) and represents the only known acetylation mark on messenger RNA. Since NAT10 also acetylates transfer RNA, ribosomal RNA (rRNA), and proteins, its in vivo molecular mechanisms remain elusive. Here, we demonstrate that knockdown of Drosophila NAT10 induces an eye-to-antenna transformation, c-Jun amino-terminal kinase activation, and cell apoptosis. NAT10 facilitates ac4C modification in rRNA, and its loss impairs rRNA processing and ribosomal assembly. Depletion of NAT10 activates the integrated stress response, ultimately leading to reduced global protein synthesis. Crucially, Xrp1 plays a key role in the stress response and its ablation rescues most NAT10 loss-of-function defects and transcriptomic alterations. We also performed acetylated RNA immunoprecipitation and sequencing (acRIP-seq) on control and NAT10 knockdown flies. Furthermore, a catalytically deficient form of NAT10, which is unable to mediate ac4C acetylation, completely rescues the lethality of NAT10 mutants. Collectively, these findings establish that NAT10's primary developmental function stems from its roles in ribosome biogenesis and Xrp1 activation, which are independent of its RNA acetylation activity.
    DOI:  https://doi.org/10.1126/sciadv.aeg0399
  6. Ann N Y Acad Sci. 2026 Oct;1564(1): e70413
    A DRACH Observed/Expected Metric Reveals the Evolutionary Landscape of Epitranscriptomic Regulation Across Bilateria.
    Natacha Clairet, Jérémy Le Luyer, Hélène Auger, Maximilian Haeussler, Guillaume Rivière.
      N6-methyladenosine (m6A) RNA modification is a dynamic post-transcriptional regulatory mechanism that rapidly modulates gene expression by influencing RNA stability, export, splicing, translation, and decay. In bilaterians, m6A is predominantly deposited at the DRACH consensus motif, which comprises 18 sequence variants. Although the presence of a DRACH motif does not indicate whether a transcript is currently, or has ever been, methylated, it reflects its potential for m6A-mediated regulation. Here, we introduce a new metric, DRACH observed/expected (DRACH o/e), to quantify the relative enrichment of DRACH motifs independently of sequence composition. We applied this approach to characterize the abundance, distribution, and genomic organization of DRACH motifs in the Pacific oyster Magallana gigas, a representative lophotrochozoan species in which m6A regulation remains poorly characterized. These analyses were extended to eight additional species spanning major bilaterian lineages and exhibiting contrasting ecological traits. Comparative analysis revealed strong conservation of the m6A regulatory machinery together with conserved and lineage-specific patterns of DRACH motif distribution and functional enrichment. This work introduces a robust framework for estimating the potential for transcript m6A methylation while overcoming the inherent variability of epitranscriptomes, thereby paving the way to explore comparative analyses of its potential phylogenetic and/or ecological drivers.
    Keywords:  DRACH sites; Magallana gigas; RNA methylation; eco‐evo‐devo; evolution; m6A; oyster
    DOI:  https://doi.org/10.1111/nyas.70413
  7. J Virol. 2026 Sep 30. e0083426
    Changes in the translational landscape during red clover necrotic mosaic virus infection.
    Pulkit Kanodia, Zachary Lozier, Filip Lastovka, David Walker, Peng Liu, Betty Chung, W Allen Miller.
      Viruses alter host gene expression to create a proviral environment, while the host simultaneously regulates gene expression to restrict viral spread. Owing to RNA viruses' complete reliance on the host translational machinery, it is important to assess translational control during virus infection. Therefore, we used ribosome profiling (Ribo-seq) paired with RNA-seq to observe how red clover necrotic mosaic virus (RCNMV) infection of Arabidopsis plants alters cellular gene expression at the levels of mRNA abundance and translation efficiency. We determined that at 5 days post-inoculation (dpi), the translational response to RCNMV infection is enriched in genes of the innate immune system. Expression of a tumor necrosis factor receptor-associated factor (TRAF)-like protein, a regulator of development and immune response, was translationally but not transcriptionally upregulated early in systemic infection. By 8 dpi, many pathways were regulated/dysregulated, and unfolded protein response (UPR) genes were transcriptionally upregulated but with reduced translation efficiency. Ribosome profiling of RCNMV RNAs revealed (i) -1 programmed ribosomal frameshifting at 7.5%-8.0%, the first direct measurement of frameshift efficiency in infected cells for any plant virus; (ii) that coat protein is translated at extremely high efficiency, while the RNA-dependent RNA polymerase is translated least efficiently; and (iii) an unexpected extremely strong ribosomal pause site in the open reading frame that encodes the movement protein. To our knowledge, this is the first genome-wide study that assesses the translational control of gene expression in plants infected with a virus from the large and diverse Tombusviridae family.IMPORTANCEPositive-strand RNA viruses usurp the host's translation machinery to synthesize viral proteins. Moreover, translation of host mRNAs is altered by virus infection, both as part of the host immune response and by the virus to inhibit host defenses. To assess all these changes globally, we used ribosome profiling of plants infected with a member of the large and ubiquitous Tombusviridae family. We identified key host genes and pathways that were differentially altered in translation efficiency, giving us an understanding of host responses not detectable by conventional RNA sequencing. Moreover, ribosome profiling revealed (i) the most accurate calculation of the efficiency of ribosomal frameshifting during infection for any plant virus, (ii) the extremely high level of translation of viral coat protein, and (iii) an unexpectedly strong ribosomal pause site in the movement protein gene. This work provides an understanding of a new dimension of gene expression control in plant-virus interactions.
    Keywords:  Ribo-seq; Tombusviridae; ribosomal frameshifting; ribosome profiling; translational control
    DOI:  https://doi.org/10.1128/jvi.00834-26
  8. Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250271. [Epub ahead of print]381(1960):
    Regulation of cellular proteostasis via mitochondrial protein import.
    Ngoc G T Nguyen, Jian Li.
      Mitochondria are the powerhouse of the cell, playing vital roles in energy production and metabolism. Most mitochondrial proteins are encoded in the nuclear DNA and must be synthesized in the cytosol before being transported into the appropriate mitochondrial compartments. Mitochondrial protein import is not only essential for mitochondrial biogenesis but also a crucial regulatory step in mitochondrial proteostasis surveillance and stress response. Additionally, defects in mitochondrial protein import lead to mislocalization of precursor proteins to the cytosol, disrupting cytosolic proteostasis and contributing to various human diseases. This review summarizes recent findings demonstrating that mitochondrial protein import is a key regulator of cellular proteostasis. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.
    Keywords:  mitochondria; protein import; proteostasis; stress response
    DOI:  https://doi.org/10.1098/rstb.2025.0271
  9. bioRxiv. 2026 Sep 22. pii: 2026.09.17.752513. [Epub ahead of print]
    Fluorescent proteins misreport ribosome abundance under translation inhibition.
    Aniket Zodage, Justin Chen, Nabigha Mogharbel, Hidde de Jong, Suckjoon Jun.
      Fluorescent proteins are widely used as quantitative reporters of protein abundance in living cells. Here we show that this relationship can break down under translation inhibition: the cellular ribosomal abundance can increase while fluorescence intensity remains unchanged or even decreases. Using fluorescent reporters of ribosome abundance in Escherichia coli and Bacillus subtilis , we find that cellular fluorescence intensity quantitatively tracks ribosome abundance, inferred by RNA-to-protein ratio, under nutrient-limited growth but that is no longer true during chloramphenicol treatment. In E. coli , the discrepancy occurs with transcriptional and translational reporters and with both ribosomal protein and ribosomal RNA promoters. To distinguish changes in fluorescence output per reporter from changes in reporter abundance, we constructed a fluorescent protein-LacZ dual reporter in which fluorescence and an independent enzymatic estimate of reporter abundance are obtained from the same protein. Under translation inhibition, LacZ-derived reporter abundance increases whereas fluorescence intensity remains approximately constant, showing that fluorescence output per unit reporter abundance decreases. In a companion study, Bakshi and colleagues demonstrate that the effect extends to other fluorescent proteins and other translation inhibitors, indicating that it is not specific to a particular fluorescent protein or translation inhibitor. Our results show that fluorescent-protein calibration can be condition-dependent and cannot be assumed to transfer across physiological perturbations.
    DOI:  https://doi.org/10.64898/2026.09.17.752513
  10. bioRxiv. 2026 Sep 25. pii: 2026.09.24.754133. [Epub ahead of print]
    Translation fidelity mechanisms and their changes in aging.
    Mauricio Aguilar Rangel, Casey Powers, Jaeyoon Lee, Haley E Tarbox, Neil B Wood, Stephen D Fried, Stephen Quake, Joseph D Puglisi.
      Protein errors (amino acid misincorporations) are associated to protein misfolding and misfunction, and lower levels correlate with longer lifespan 1 . Despite their prevalence, proteome-wide tracking of misincorporations in eukaryotes is challenging, with most insights being recent and coming from the mining of extensive proteomics data sets 2-5 . These experimental challenges have precluded the direct in vivo probing and full understanding of the bases of fidelity in higher eukaryotes, and their influence in complex processes such as aging. Here we measured proteome-wide misincorporation frequencies in two experimentally tractable eukaryotic systems, yeast and mouse, using mass spectrometry. We find translation fidelity is organism and organ specific. The measured error frequencies correlate with codon:anticodon pairing thermodynamics and tRNA pool composition, which can have synergistic or opposing effects on fidelity depending on organism or tissue type. Most identified protein errors carry a negative fitness burden. Aging experiments in our two systems reveal that, with age, error frequencies increase in post-mitotic cells, but not so in mitotic ones. These changes correlate with remodeling of the tRNA pool, which we identify as a crucial regulator of translation fidelity during lifespan.
    DOI:  https://doi.org/10.64898/2026.09.24.754133
  11. mBio. 2026 Oct 02. e0205626
    A small molecule increases mycobacterial translation fidelity without a fitness cost by targeting ribosomal protein S5.
    Jie Wu, Swarnava Chaudhuri, Sarah Caldwell Feid, Hemant Joshi, Miaomiao Pan, Qingwen Kawaji, Gang Liu, Babak Javid.
      A central dogma of molecular biology is the "speed-accuracy trade-off," where ribosomes must slow down to ensure accurate protein synthesis. In mycobacteria, a high basal level of mistranslation at glutamine and asparagine codons, caused by an indirect tRNA aminoacylation pathway, promotes tolerance to the antibiotic rifampicin. While pharmacologically increasing translational fidelity is a promising strategy to combat antibiotic tolerance, the underlying mechanisms remain poorly understood. Here, we screened 9,000 synthetic compounds and identified benzo[d]isoxazole-4,7-diones as a novel chemical class that reduces mycobacterial mistranslation. Medicinal chemistry optimization yielded a lead compound, 9787, with superior potency in decreasing mistranslation and reversing rifampicin tolerance. Using competitive chemical proteomics, we identified the 30S ribosomal protein S5 (RpS5) as the specific cellular target. Remarkably, compound 9787 enhances translational fidelity at concentrations that do not measurably impact the overall rate of protein synthesis. Our findings challenge the universality of the speed-accuracy trade-off, demonstrating that fidelity can be improved independently of translation speed. This work reveals that the ribosomal small subunit is a druggable target for modulating translational quality control, and introduces a new strategy for combating antibiotic-tolerant bacteria without the associated fitness cost of slowed translation.IMPORTANCEA fundamental principle in molecular biology holds that ribosomes face a trade-off between translation speed and accuracy: going faster means making more errors, while maintaining high fidelity requires slowing down. This study challenges that paradigm by identifying a small molecule that increases translational accuracy in mycobacteria without affecting the rate of protein synthesis. The compound targets ribosomal protein S5 and specifically reduces errors arising from physiologically mischarged tRNAs-a quality control problem distinct from the well-studied codon-anticodon mismatches. This form of mistranslation contributes to antibiotic tolerance in tuberculosis, making it a potential therapeutic target. Our findings reveal unexpected flexibility in how ribosomes maintain translation quality and suggest that pharmacologically increasing fidelity without the fitness cost of slowed protein synthesis may be an attractive strategy for combating antibiotic-tolerant bacteria.
    Keywords:  antibiotic tolerance; medicinal chemistry; mistranslation; mycobacteria; small molecule; translational fidelity
    DOI:  https://doi.org/10.1128/mbio.02056-26
  12. EMBO J. 2026 Oct 02.
    A conserved archaeal protein with evolutionary links to bacterial ribosome hibernation and eukaryotic energy sensing.
    Diorge P Souza, Mira B May, Jackson Carrion, Vikram Alva, Alex Bisson, Joseph H Davis.
      Ribosome hibernation helps cells survive stress by reversibly silencing translation and preserving ribosomal complexes. Although well characterized in bacteria and eukaryotes, archaeal hibernation remains poorly understood. Using cryoEM of archaeal lysates, we identified AHA (AMPKγ-HPF from Archaea), a broadly conserved ribosome-associated factor composed of two modules. AHA bound across ribosomal subunits, occluding the mRNA channel and tRNA binding sites, supporting its role in ribosome hibernation. ΔAHA cells displayed reduced viability, loss of ribosomal proteins in the stationary phase, and impaired growth reentry in rich media. Phylogenetic analyses revealed that AHA's C-terminal domain is homologous to the bacterial Hibernation Promoting Factor (HPF), consistent with inheritance from the last universal common ancestor and thereby identifying HPF as a universal hibernation module in prokaryotes. Strikingly, we observed two AMP molecules bound to AHA's N-terminal CBS-tetrad, which showed both sequence and structural similarity to the eukaryotic energy sensor AMPKγ, supporting a shared evolutionary origin of the archaeal CBS-tetrad and the AMPKγ family. Together, these findings uncover a widespread archaeal ribosome hibernation factor and reveal an evolutionary connection between prokaryotic ribosomal hibernation and eukaryotic energy sensing.
    DOI:  https://doi.org/10.1038/s44318-026-00918-6
  13. Cancer Res. 2026 Oct 02.
    EZH2 Inhibition Induces a Metabolic Stress Response Sensitizing Triple-Negative Breast Cancer to Glutaminase Targeting.
    Lucas Porras, Marina Carrière, Ann-Sophie Gironne, Hugo Philippeau, Gabriel Alzial, Elise Quadri, Jeanne Cormery, Yousef Alaessa, Anie Monast, Faustine Gorse, Myriame St-Arnaud, Mariana De Sa Tavares Russo, Sylvie Nathalie Christine Mader, Daina Z Avizonis, Sébastien Lemieux, Morag Park, Geneviève Deblois.
      EZH2, the catalytic subunit of the histone methyltransferase complex PRC2, is overexpressed and associated with poor prognosis in triple-negative breast cancer (TNBC). Although EZH2 inhibition significantly alters chromatin landscapes and gene expression, it has limited impact on the growth of TNBC models, suggesting adaptive compensatory mechanisms. Here, we demonstrated that EZH2 inhibition causes the accumulation of misfolded proteins and double-stranded RNA (dsRNA), triggering an essential integrated stress response (ISR) through PKR and PERK activation. By inducing ISR-mediated ATF4, EZH2 inhibition enhanced amino acid flux and promoted glutaminolysis to support TNBC cell survival. Pharmacological targeting of this metabolic axis with a glutaminase inhibitor in combination with EZH2 inhibition significantly impaired TNBC cell proliferation and tumor growth. These findings reveal a stress-driven metabolic adaptation that sustains TNBC survival upon EZH2 blockade and highlight inhibition of this pathway as a strategy to enhance the efficacy of EZH2 inhibitors in TNBC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-0801
  14. Cancer Treat Res Commun. 2026 Sep 29. pii: S2468-2942(26)00367-9. [Epub ahead of print]49 101457
    Post-translational acylation of proteins in colorectal cancer.
    Fan Xu, Shuoshuo Wang, Yunting Le, Chen Chen, Minghui Zhang, Jing Tang.
      Accumulating preclinical evidence indicates that protein acylation, a functionally diverse class of post-translational modifications, is implicated in the regulation of protein stability, enzymatic activity, subcellular localization, molecular interactions, and gene transcription. In colorectal cancer (CRC), this modification family has been linked to proliferation, invasion, metastasis, metabolic reprogramming, therapeutic resistance, and immune escape. This review critically summarizes recent advances in five major acylation types associated with CRC: crotonylation, succinylation, lactylation, acetylation, and palmitoylation. We distinguish histone-mediated transcriptional regulation from the direct functional effects of non-histone acylation, and evaluate the mechanistic evidence linking specific modification sites and regulatory enzymes to CRC phenotypes. We also discuss crosstalk between acylation and other post-translational modifications, current detection strategies, and the proposed translational potential of acylation-associated molecules as biomarkers or therapeutic targets. Most available supporting evidence is derived from cell lines and animal models, whereas validation in patient-derived organoids, independent clinical cohorts, and prospective studies remains incompletely characterized. Establishing causality and defining the clinical relevance of protein acylation in CRC will require further studies integrating site-specific mutagenesis, enzyme perturbation, orthogonal detection methods, and physiologically relevant models. Collectively, the reviewed body of work frames protein acylation as a biologically relevant regulatory axis in CRC, while underscoring that additional rigorous investigation is needed to realize its translational potential.
    Keywords:  Acetylation; Crotonylation; Lactylation; Palmitoylation; Succinylation
    DOI:  https://doi.org/10.1016/j.ctarc.2026.101457
  15. bioRxiv. 2026 Sep 23. pii: 2026.09.22.753649. [Epub ahead of print]
    Tracking cellular biomolecular condensate dynamics under proteostatic stress with middle-down phosphoproteomics.
    Boomathi Pandi, Dominic C M Ng, Peyton Schaal, Lorena Alamillo, Shaonil Binti, Edward Lau, Maggie P Y Lam.
      Coordination of biological function requires the partition of cellular components including into biomolecular condensates, but an overall landscape of how protein compartmentalize into higher-order assemblies under stress is still emerging. We apply proteome-wide solubility profiling to compare the compositions of NP-40-insoluble proteins and their phosphorylation status, using a new mass spectrometry-based hybrid bottom-up and chemical middle-down proteomics approach to analyze the solubility behavior of 8,740 proteins and 31,647 phosphopeptides under normal and ER stress conditions. Cell stress induces a pervasive differential partition of proteins in and out of detergent- insoluble cellular compartments. This differential partition is partially orthogonal to stress-induced abundance changes and comprises both phosphorylation-dependent and phosphorylation-independent mechanisms. Whereas phosphorylation-independent partition changes involve largely secretory pathway proteins and implicate higher-order assemblies of chaperones and clients, phosphorylation-based partitions suggest a dynamic rearrangement of biomolecular condensate compositions across cytoplasmic and nuclear ribonucleoprotein assemblies. The accumulation of serine/arginine rich (SR) proteins and other annotated nuclear speckle members in the condensate-rich proteome fractions emerges as a central feature of stress-induced remodeling. Our results establish global solubility dynamics as an integral component of proteome stress response and implicates broad involvements of splice factor spatial reorganization as a prominent facet of ER stress response.
    DOI:  https://doi.org/10.64898/2026.09.22.753649
  16. Eur J Cell Biol. 2026 Sep 25. pii: S0171-9335(26)00047-6. [Epub ahead of print]105(4): 151576
    ATF3: Friend or foe in cellular stress and repair? A context-dependent stress rheostat framework.
    Rong Huang, Ruikang Li, Phei Er Saw, Mao Zhou.
      Activating transcription factor 3 (ATF3) is an immediate-early basic leucine zipper transcription factor induced by diverse forms of cellular stress. Although ATF3 is often described as a "double-edged sword," that formulation alone does not explain why the same stress-responsive factor can accompany successful adaptation, regeneration, inflammation resolution, cell death, fibrosis, or tumor progression. Here, we synthesize evidence across neuronal injury, innate immunity, cardiovascular and metabolic stress, cancer, and fibrotic disease and propose that ATF3 is better understood as a context-dependent stress rheostat. We organize ATF3 biology around two complementary principles: a temporal/intensity threshold model, in which the duration and magnitude of the stress response influence whether ATF3 is embedded in adaptive or unresolved pathological programs, and a partner/context-switch model, in which transcriptional output is redirected by cell identity, interacting transcription factors, chromatin state, and the surrounding signaling environment. This framework resolves several apparent contradictions in literature. Transient ATF3 induction can enhance neuronal growth competence, restrain Toll-like receptor (TLR) signaling, and support tissue adaptation, whereas sustained or disease-specific ATF3 programs can contribute to metabolic dysfunction, fibrotic remodeling, or tumor invasion. Importantly, ATF3 expression should not be equated with ATF3 causality: in several settings it marks a stressed cell state while cell fate is determined by additional signaling nodes. We therefore critically evaluate translation. ATF3 is well established as an experimental marker of neuronal and tissue stress, but its broad inducibility, intracellular localization, temporal variability, and cell-state dependence limit its current value as a stand-alone clinical biomarker. Similarly, global activation or inhibition is unlikely to be a generally safe therapeutic strategy. Future development should prioritize cell-resolved ATF3 activity signatures, temporal pharmacodynamic measurements, and context-selective interventions that target the specific ATF3-centered network operating in a defined disease state.
    Keywords:  Activating transcription factor 3; Biomarker; Cellular stress; Injury and repair; Integrated stress response; Stress rheostat
    DOI:  https://doi.org/10.1016/j.ejcb.2026.151576
  17. NAR Cancer. 2026 Dec;8(4): zcag027
    N6-methyladenosine promotes temozolomide resistance through mRNA stabilization in glioblastoma cells.
    Emily A Dangelmaier, Dorthy Fang, Isabel P Hardy, Kyal Sin Htet, Nicole S Harry, Renee Pascoe, Je Won Yang, Clara D Wang, Sigrid Nachtergaele.
      N6-methyladenosine (m6A) regulates nearly every aspect of messenger RNA (mRNA) processing and function, impacting downstream gene expression programs. Changes in m6A have been implicated in many different types of cancer, and inhibition of m6A installation is emerging as a cancer therapeutic strategy. However, chemoresistance remains a significant clinical challenge in the treatment of glioblastoma (GBM). We established GBM cell culture models of acquired temozolomide (TMZ) resistance, analyzed the role of m6A in controlling resistance-associated pathways, and assessed the effects of METTL3 inhibition. We show that m6A stabilizes key genes and pathways promoting TMZ resistance, and that METTL3 inhibition can reverse this and restore TMZ sensitivity. These findings highlight that TMZ resistance can occur independent of a glioma stem cell population and that changes in m6A need not be driven by changes in METTL3 expression. Collectively, our results suggest that genes associated with TMZ resistance are stabilized by m6A methylation even as the majority of the transcriptome remains subject to m6A-mediated mRNA decay. Moreover, these data highlight METTL3 inhibition as a promising therapeutic approach to overcoming TMZ resistance in GBM.
    DOI:  https://doi.org/10.1093/narcan/zcag027
  18. Crit Rev Oncol Hematol. 2026 Sep 28. pii: S1040-8428(26)00512-3. [Epub ahead of print] 105625
    From Translation Milestones to Clinical Breakthroughs: Decision-Making Hubs and Translational Strategies for RNA-Binding Proteins in the Immunotherapy of Haematological Malignancies.
    Peng Liu, Jingjing Liu.
      Immunotherapy for haematological malignancies-including CAR-T and immune checkpoint inhibitors-is limited by resistance driven by rapid adaptive changes at the tumour-immune interface that transcriptional regulation cannot address. This review introduces 'translational checkpoints' as a synthesized working framework for overcoming resistance by targeting RNA-binding proteins (RBPs) that govern rapid protein synthesis in tumour and immune cells. We address three core questions: how tumours evade immune surveillance, how immune dysfunction arises, and how to develop targeted interventions. We cover the molecular basis of translational checkpoints, tumour-intrinsic checkpoints (IGF2BP-mediated antigen silencing, CSDE1-driven neutralisation of innate immunity, RNF220/FXR1-mediated metabolic remodelling, and the csNPM1 cell-surface checkpoint), immune cell-intrinsic checkpoints (haematopoietic stem cell fate regulation, LARP4-driven T-cell exhaustion, and the dual role of YTHDF2 in B-cell transformation), and RNA modification-RBP networks. Based on the 'RBP-mediated bidirectional checkpoint model', we establish a four-subtype diagnostic stratification system and propose five actionable therapeutic strategies-including LARP4 gene-edited CAR-T, YTHDF2 inhibitors plus CAR-T, and csNPM1-targeting antibodies. All recommendations are annotated with evidence strength, and timelines are speculative, conditional on preclinical-to-clinical progression. This framework provides a practical roadmap for patient stratification and precision immunotherapy. The 'translational checkpoint' is a synthesized conceptual framework from aggregated preclinical data, not an established nomenclature. Key knowledge gaps remain: RBP redundancy, context-dependent dual functions of YTHDF2 and CSDE1, and cell-type-specific effects in primary human haematopoietic tissue.
    Keywords:  CAR-T cells; RNA-binding proteins; clinical translation; haematological malignancies; immunotherapy; spatiotemporal translational reprogramming; translation checkpoints
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105625
  19. Nucleic Acids Res. 2026 Sep 22. pii: gkag916. [Epub ahead of print]54(18):
    Site-specific inhibition of translation initiation via 2'-O-methylation.
    Adam Suh, Stephanie Mou, Emmely A Patrasso, Hannah Serio, Rui Wang, Yue Zhao, Kevin Vasquez, Smriti Sangwan, Yang Yi, Daniel Arango.
      Translation initiation involves a concerted set of intermolecular interactions that efficiently recognize optimal AUG start codons. However, translation initiation complexes often start at upstream non-optimal AUGs or near-cognate codons, leading to the expression of upstream open reading frames (uORFs). Using retrospective analyses of translation preinitiation cryo-EM structures, we identified putative hydrogen bonds between the 2'-OH groups of messenger RNA (mRNA) start codons with 18S ribosomal RNA. Disruption of these interactions using a chemical modification of mRNA, 2'-O-methylation (Nm), repressed translation initiation by preventing the preinitiation complex from recognizing start codons. Notably, 2'-O-methylation in upstream AUG and near-cognate codons inhibits upstream translation initiation while enhancing the expression of canonical ORFs. These findings revealed a transcript- and site-specific inhibitory role for 2'-O-methylation in translation initiation, providing novel insights into the mechanisms of start codon selection in human transcriptomes.
    DOI:  https://doi.org/10.1093/nar/gkag916
  20. Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250274. [Epub ahead of print]381(1960):
    Adaptation to heat stress by diversification of the vertebrate heat shock transcription factor family.
    Ryosuke Takii, Mitsuaki Fujimoto, Akira Nakai.
      Cells survive and reproduce by coping with acute or chronic exposure to a fixed elevated temperature or fluctuating temperatures. These properties are one of the main evolutionary forces and involve the heat shock response. This response is characterized by the induction of heat-shock proteins (HSPs) and is mainly regulated by heat-shock transcription factors (HSFs) in vertebrates. A single HSF is present in yeast and invertebrates, such as Caenorhabditis elegans and Drosophila, whereas vertebrates have evolved multiple HSFs. The potential of HSFs to induce HSP expression is linked to the amino acid conservation of their domains and regions that are responsible for transcriptional activation and appears to be associated with the homeothermic capacity of vertebrate animals in a thermally fluctuating environment. HSFs protect cells and organisms from heat stress by regulating not only their expression of HSPs that assist in protein folding and suppress protein misfolding and aggregation, but also the expression of genes related to protein clearance, metabolism, the cell cycle, DNA damage response, apoptosis, senescence, the cytoskeleton, extracellular matrix and inflammation. The diversification of HSF genes may expand the cellular capacity to adapt to thermal changes in vertebrate animals. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.
    Keywords:  HSF; body temperature; evolution; heat resistance; heat shock; vertebrate
    DOI:  https://doi.org/10.1098/rstb.2025.0274
  21. CNS Neurosci Ther. 2026 Oct;32(10): e71164
    METTL3 Increases Temozolomide Resistance in MGMT-Negative Glioblastoma by Enhancing CBX5 mRNA Stability in an m6A-IGF2BP2-Dependent Manner.
    Hui Deng, Ruoyu Chen, Daohong Qu, Cifu Qu, Jia Shi.
       AIMS: We examined whether chromobox protein 5 (CBX5) contributes to temozolomide (TMZ) resistance in O6-methylguanine-DNA methyltransferase (MGMT)-negative glioblastoma (GBM) and whether it is regulated by methyltransferase-like 3 (METTL3)-dependent N6-methyladenosine (m6A) and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2).
    METHODS: Public datasets, clinical specimens, MGMT-negative cells, and subcutaneous xenografts were examined using functional, mechanistic, and rescue assays.
    RESULTS: In the CGGA693 cohort of the Chinese Glioma Genome Atlas, higher CBX5 expression remained associated with shorter survival after multivariable adjustment (hazard ratio 1.178, 95% confidence interval 1.050-1.322; p = 0.005). CBX5 depletion increased TMZ sensitivity, apoptosis, and DNA damage, reduced ATM phosphorylation and RAD51 abundance, and restricted TMZ-treated xenograft growth; overexpression produced reciprocal effects in vitro. METTL3 depletion reduced CBX5 expression, mRNA stability, m6A enrichment, and wild-type reporter activity but did not significantly affect the m6A motif-mutant reporter. IGF2BP2 depletion reduced CBX5 protein and mRNA stability, whereas RNA immunoprecipitation supported an IGF2BP2-CBX5 mRNA association. CBX5 re-expression partially reversed METTL3 depletion-induced effects on viability and DNA damage.
    CONCLUSION: METTL3-dependent m6A modification and IGF2BP2-associated stabilization help maintain CBX5 expression, contributing to TMZ resistance and ATM-RAD51-associated signaling in MGMT-negative GBM models.
    Keywords:  CBX5; IGF2BP2; METTL3; N6‐methyladenosine; glioblastoma; temozolomide resistance
    DOI:  https://doi.org/10.1002/cns.71164
  22. Cancer Sci. 2026 Sep 29.
    PABPC1 in Cancer: From a Translational Housekeeper to a Stress-Responsive Regulatory Hub.
    Cuiwei Zhang, Ye Zhu, Wenbo Long.
      PABPC1, long recognized as a constitutive translational housekeeper, has emerged as a stress-responsive translational reprogramming hub in cancer. This review synthesizes recent paradigm shifts that redefine PABPC1 function: From global translation maintenance to selective oncogenic mRNA amplification via liquid-liquid phase separation; from binary protein-RNA interactions to complex regulatory networks involving lncRNAs and circRNAs that modulate PABPC1 stability, localization, and target selectivity; and from diffuse cytoplasmic distribution to functionally compartmentalized condensates. PABPC1 integrates diverse post-translational modifications, including SUMOylation, acetylation, and ubiquitination, that enable stress adaptation, and actively regulates alternative polyadenylation to influence 3'UTR length and gene expression. Positioned at the convergence point of multiple oncogenic signaling pathways (PI3K/AKT, Wnt/β-catenin, NF-κB, and etc.), PABPC1 converts upstream signals into translational outputs that drive tumor progression, metastasis, and therapy resistance across malignancies. Its functional duality, context-dependent activities, and paralog-specific roles underscore both the complexity and therapeutic potential of targeting this multifaceted RNA-binding protein.
    Keywords:  poly(a)‐binding protein cytoplasmic 1 (PABPC1); post‐translational modification; stress resistance; therapy resistance; translation regulation
    DOI:  https://doi.org/10.1111/cas.70549
  23. Mol Ecol. 2026 Oct;35(19): e70553
    Polyphenism Through RNA Chemical Modifications.
    Ralf Schneider, Ehsan Pashay Ahi.
      Polyphenism, the capacity of a single genotype to produce discrete phenotypes in response to environmental cues, has long served as a model for understanding developmental plasticity. While classical studies have highlighted hormonal signalling and transcription-factor-driven gene regulatory networks that mediate these environmentally induced shifts, recent advances have uncovered a new layer of gene regulation through chemical modifications of RNA molecules. These RNA modifications, collectively known as epitranscriptomic marks, have been shown to respond to environmental signals and modulate RNA fate. Despite their regulatory potential, their involvement in polyphenic systems remains largely unexplored. Here, we synthesize evidence suggesting that RNA modifications may form a dynamic, context-sensitive interface linking environmental inputs to phenotypic expression and developmental commitment in polyphenic systems.
    Keywords:  Epitranscriptomics; Polyphenism; RNA modifications; environmental regulation; phenotypic plasticity
    DOI:  https://doi.org/10.1111/mec.70553
  24. Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250267. [Epub ahead of print]381(1960):
    Disruption of RNA metabolism and its impact on protein homeostasis.
    Susana M D A Garcia.
      Repeat-associated disorders arise from expansions of nucleotide repeats in coding or non-coding regions, producing RNAs that accumulate and disrupt cellular homeostasis through mechanisms collectively termed RNA repeat toxicity. This process complements proteotoxicity in coding-region expansions and is increasingly recognized as a major contributor to pathogenesis. Expanded repeat RNAs form stable secondary structures that sequester RNA-binding proteins (RBPs), such as Muscleblind-like, alter splicing and activate small RNA pathways, broadly impacting gene expression. Myotonic dystrophy type 1 (DM1) exemplifies RNA-mediated toxicity, with expanded CUG repeats in the DMPK 3' untranslated region driving nuclear foci formation, RBP sequestration and transcriptome-wide changes. Beyond RNA processing defects, DM1 exhibits systemic dysfunction, notably affecting energy metabolism and mitochondrial function, which recent evidence suggests may be disrupted early and progressively during disease development. These metabolic changes intersect with proteostasis failure, amplifying cellular stress and contributing to systemic pathology. A deeper understanding of the molecular networks that drive metabolic and mitochondrial dysfunction, and their role in proteostasis collapse, will be critical for elucidating disease onset and progression. This knowledge will enable the identification of novel therapeutic targets and biomarkers, offering strategies that go beyond RNA-centric approaches to restore cellular homeostasis in repeat-based disorders. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.
    Keywords:   Caenorhabditis elegans ; RNA repeat toxicity; energy metabolism; mitochondria; myotonic dystrophy; proteostasis
    DOI:  https://doi.org/10.1098/rstb.2025.0267
  25. Front Immunol. 2026 ;17 1889279
    mRNA processing in cancer immunotherapy: emerging targets, resistance mechanisms, and therapeutic opportunities.
    Yunus Yukselten, Haseeb Ahmad, Mohammed Shoultout, Uzair Iqbal, Faizan Masood, Richard E Sutton.
      Cancer immunotherapy has improved outcomes across many tumor types, but primary and acquired resistance, tumor heterogeneity and a shortage of safe targets remain unresolved. Part of this gap arises because tumor cells evade immune recognition not only through genomic mutation but also through post-transcriptional mRNA processing, a network comprising 5' capping, splicing, alternative polyadenylation (APA), RNA editing, epitranscriptomic modification, nonsense-mediated decay (NMD), RNA stability and translational control. These processes govern antigen presentation, transcript degradation, checkpoint expression and the suppression of innate immune sensing. Here we examine how mRNA processing can extend the target space of cancer immunotherapy. We consider alternative splicing as a source of tumor-specific isoforms, public neoantigens and chimeric antigen receptor (CAR) or T-cell receptor (TCR)-based targets; the effect of APA and 3'UTR remodeling on checkpoints such as PD-L1; the role of m6A, ac4C and other epitranscriptomic marks in antigen presentation, interferon signaling and the tumor microenvironment; the contribution of ADAR1-mediated editing to immunotherapy resistance through suppressed dsRNA and Z-RNA sensing; and the function of NMD as an antigen filter. We also review the discovery technologies that make these targets accessible, and assess the current state of clinical translation, including agent development, target specificity, patient selection, biomarkers and safety. mRNA processing-derived targets offer new sources of antigens, biomarkers and combination strategies in tumors with low mutational burden or refractory to checkpoint blockade. Realizing this will require validation of RNA-level candidates at the protein and HLA-peptide level, together with attention to tumor-normal specificity, HLA restriction, tumor heterogeneity and toxicity.
    Keywords:  3′UTR remodeling; RNA editing; cancer immunotherapy; chemokines; epitranscriptomics; immunopeptidomics; mRNA processing; splicing-derived neoantigens
    DOI:  https://doi.org/10.3389/fimmu.2026.1889279
  26. bioRxiv. 2026 Sep 27. pii: 2026.09.25.754360. [Epub ahead of print]
    Sex-specific metabolic regulation by the Drosophila RNA-binding protein Nab2.
    Jordan N Goldy, Heath Dunlop, Dev D Patel, Rebecca M McSweeney, Sara W Leung, David U Gorkin, Anita H Corbett, Ken Moberg.
      Conserved RNA binding proteins (RBPs) regulate key steps of gene expression including mRNA processing, export, localization, stability and translation. Human ZC3H14 is a conserved RBP that regulates pre-mRNA processing in neurons and loss of ZC3H14 leads to neurological defects. Studies of Nab2, the Drosophila orthologue of ZC3H14, have identified potential target RNAs involved in metabolism, suggesting Nab2 may influence neurometabolic circuitry. Here, we show a female-specific increase in dilp2 and dilp5 mRNA levels. The dilps encode insulin-like peptides that signal from the brain insulin producing cells (IPCs) to peripheral tissues. Nab2null females have enlarged lipid droplets in the fat body, a tissue analogous to human adipose tissue and liver. Notably, neuronal depletion of Nab2 increases lipid droplet size while neuronal expression of Nab2 in Nab2null female rescues this phenotype supporting a role for Nab2 in a neuronal circuit that regulates dilp levels. Furthermore, depletion of dilp2 or dilp5 from IPCs rescues the enlarged lipid droplet phenotype in Nab2null females indicating that elevated dilp2/dilp5 contributes to enlarged lipid droplets. Together, these data support a female-specific role for Nab2 in brain neurons to support insulin signaling and fat storage, expanding the known functions of RBPs linking neuronal function and metabolic homeostasis.
    DOI:  https://doi.org/10.64898/2026.09.25.754360
  27. Crit Rev Oncol Hematol. 2026 Oct 02. pii: S1040-8428(26)00510-X. [Epub ahead of print] 105623
    Mechanistic Role of eIF4E in the Hallmarks of Cancer: A Translational Control Perspective.
    Magdalene Eno Udobi, Paul Etim Effiong, Sumon Roy, Chibuike Emmanuel Okafor, Joseph M Schober, Lionel In Lian Aun, Bhargav A Patel.
      Cancer progression is driven by coordinated dysregulation of signaling and gene-expression programs that sustain multiple hallmarks of malignancy. Eukaryotic initiation factor 4E (eIF4E) has emerged as an important determinant of this translational reprogramming by preferentially enhancing the synthesis of proteins that support oncogenic phenotypes. This review critically examines the mechanistic evidence linking eIF4E-dependent translation to major cancer hallmarks, including sustained proliferative signaling, evasion of apoptosis, tumor-promoting inflammation, angiogenesis, invasion, and metastasis. We discuss how dysregulated eIF4E activity, driven in part by the PI3K/AKT/mTOR and MAPK/MNK pathways, promotes selective translation of oncogenic, survival, stress-response, hypoxia-, and epithelial-mesenchymal transition-associated factors. We further examine evidence implicating eIF4E in the regulation of p53- and telomerase reverse transcriptase (TERT)-dependent pathways, highlighting potential links to genomic instability and replicative immortality. Finally, we evaluate pharmacological strategies targeting eIF4E and discuss the opportunities and challenges of exploiting eIF4E-dependent translational and metabolic vulnerabilities for cancer therapy. Collectively, the evidence supports eIF4E as a therapeutically relevant translational regulator whose functional activity, rather than expression alone, may help define tumor dependencies and inform mechanism-based therapeutic strategies.
    Keywords:  Cancer hallmarks; Cap-dependent translation; Precision oncology; Therapeutic targeting; eIF4E
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105623
  28. Front Endocrinol (Lausanne). 2026 ;17 1885104
    GDF15 as a sentinel of metabolic integrity: a narrative review of stress signaling, multisystem pathophysiology, and therapeutic potential.
    Tao Nie, Hongmei Song, Xiaofang Shen, Liufeng Mao.
      Growth differentiation factor 15 (GDF15) is a stress responsive cytokine belonging to the transforming growth factor-β (TGF-β) superfamily, serving as a sentinel of metabolic integrity. Its expression is induced by multiple convergent stress pathways, including the integrated stress response (ISR), endoplasmic reticulum (ER) stress, oxidative stress, inflammation, and hypoxia. GDF15 is secreted by a wide range of organs, such as adipose tissue, skeletal muscle, liver, heart, kidney, immune cells, and the central nervous system, with the relative contribution of each tissue varying across different physiological and pathological states. Through the hindbrain GFRAL-RET axis, GDF15 suppresses appetite and regulates energy balance, while also exerting peripheral effects on mitochondrial function, insulin sensitivity, and inflammatory responses. Transient GDF15 elevation in response to acute stressors supports adaptive metabolic resilience and tissue protection. In contrast, chronic and sustained elevation signals progressive metabolic dysfunction, organ impairment, and poor prognosis in conditions including obesity, metabolic dysfunction associated steatotic liver disease (MASLD), diabetes, and cardiovascular disease. Importantly, the biological impact of GDF15 is modified by factors such as age and metabolic context, which may shift the balance between adaptive and maladaptive outcomes and account for much of the predictive signal in clinical studies. Although GDF15 holds promise as a prognostic biomarker and a therapeutic target, its clinical translation is hindered by two major challenges: its dual protective and pathological roles, and an incomplete understanding of non-GFRAL signaling pathways. This narrative review summarizes the regulatory networks, tissue sources, and context-dependent functions of GDF15, with an emphasis on its roles in cardiometabolic homeostasis and the potential for future precision therapeutic strategies. We present the sentinel model as a working hypothesis that generates testable predictions, rather than as a proven biological mechanism. The acute-adaptive versus chronic-maladaptive distinction, while conceptually useful, requires validation through measurable parameters including concentration thresholds, temporal dynamics, and tissue specific contributions.
    Keywords:  GDF15; GFRAL; cardiometabolic disease; metabolic integrity; obesity
    DOI:  https://doi.org/10.3389/fendo.2026.1885104
  29. bioRxiv. 2026 Sep 24. pii: 2026.09.23.753862. [Epub ahead of print]
    Collided ribosomes are rescued by the endonuclease Rae1 and trans- translation.
    Daniel D Tetreault, Katrina Callan, Cassidy R Prince, Heather A Feaga.
      Ribosome stalling is a major problem in all domains of life. When a ribosome stalls, trailing ribosomes may catch up to and collide with the stalled ribosome, depleting protein synthesis capacity. Here, we describe a novel pathway used by Gram-positive bacteria to rescue ribosome collisions. We used the ATPase defective ABCF protein YdiF(EQ 2 ) to induce ribosome stalling and collisions in Bacillus subtilis . Ribosome profiling (Ribo-seq) of YdiF(EQ 2 )-expressing cells revealed that collided ribosomes are enriched for tmRNA, a functional RNA involved in trans -translation. We confirmed that tmRNA tagging activity is globally increased upon expression of any ATPase defective ABCF as well as in cells treated with the collision-inducing antibiotic erythromycin, suggesting this is a generalizable mechanism to rescue stalled and collided ribosomes. The global increase in tmRNA tagging that occurred in response to both erythromycin and YdiF(EQ2) induced collisions was dependent on the Rae1 endonuclease. Loss of trans -translation in cells experiencing widespread ribosome collisions leads to a severe fitness defect, consistent with the importance of this pathway in rescuing ribosomes stalled on truncated mRNAs that result from ribosome collisions. Altogether, our work supports a model in which Rae1 cleaves mRNA on collided ribosomes, thereby generating a truncated mRNA substrate for trans -translation and leading to rescue and recycling of the collided ribosomes. We term this mechanism C ollision- A ssociated R ae1-induced trans- Translation (CART). CART broadens the repertoire of tools that bacteria use to manage ribosome collisions.
    Significance: Prolonged ribosome stalling leads to ribosome collisions, which are rescued by specialized factors. While ribosome collisions have been extensively studied in eukaryotes, our understanding of collision rescue in bacteria is in its infancy. Data described here are the first to directly show that tmRNA mediates rescue of collided ribosomes in a Gram-positive bacterium, Bacillus subtilis . This pathway is analogous to what occurs in model organisms such as Escherichia coli and Saccharomyces cerevisiae , but relies on an unrelated nuclease, Rae1. Since B. subtilis and E. coli are on opposite ends of the bacterial phylogenetic tree, and since Rae1 is broadly conserved in bacteria, our findings suggest that mRNA cleavage arose convergently in distantly related bacteria as a strategy to rescue ribosome collisions. Convergent evolution of these pathways highlights the importance of rescuing collided ribosomes in all organisms. Moreover, insights into ribosome rescue in E. coli and B. subtilis can guide studies of ribosome rescue in bacteria with intermediary phylogenetic relatedness to these two model organisms.
    DOI:  https://doi.org/10.64898/2026.09.23.753862
  30. Integr Biol (Camb). 2026 Jan 16. pii: zyag022. [Epub ahead of print]18
    METTL3-m6A-mediated downregulation of IGFBP6 accelerates atherosclerotic plaque formation through GPX4-induced ferroptosis.
    Zhenzhen Liu, Yanru He, Wenjing Zhu.
      Insulin-like growth factor binding protein 6 (IGFBP6) is thought to be associated with the progression of atherosclerosis (AS). However, whether IGFBP6 is involved in ferroptosis, a key biological process, in the progression of AS remains unclear. In this study, IGFBP6 expression was downregulated in oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs). Overexpression of IGFBP6 inhibited reactive oxygen species (ROS) production, reduced Fe2+ concentration and and inflammatory factor levels, and increased Glutathione (GSH) content in ox-LDL-treated HUVECs. Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, reversed IGFBP6 silencing induced ferroptosis of HUVECs. Mechanistic studies revealed that IGFBP6 is a target of Methyltransferase-like protein 3 (METTL3) that mediates N6-methyladenosine (m6A) modification, and YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) recognizes and promotes METTL3-m6A-mediated IGFBP6 mRNA degradation. Downregulated IGFBP6 reduces its protein level by interacting with GPX4, thereby promoting ferroptosis in HUVECs. In addition, APOE-/- mice fed with a high-fat diet were used as an AS animal model, and the results showed that endothelial cell specific METTL3 knockdown or IGFBP6 overexpression hindered the development of AS in mice. In conclusion, knockdown of METTL3 inhibited the degradation of IGFBP6 mRNA in a YTHDF2 dependent manner, thereby inhibiting GPX4-mediated ferroptosis and alleviating AS progression. Insight Box This study provided new molecular targets for the effective treatment of AS. In this study, we constructed an AS cell model and an AS mouse model to explore whether METTL3 affects ferroptosis of HUVECs by regulating IGFBP6 expression through m6A modification through gain of function and loss of function experiments of METTL3 and IGFBP6, thus revealing the molecular mechanism of its involvement in the occurrence and development of AS. Results showed that METTL3 induced GPX4-mediated ferroptosis in HUVECs through m6A-YTHDF2-dependent downregulation of IGFBP6, thereby promoting the progression of AS. These findings suggest that interfering with the METTL3/YTHDF2/IGFBP6/GPX4 axis with small molecules or gene therapy may be a new strategy to intervene the occurrence and development of AS.
    Keywords:  IGFBP6; METTL3; atherosclerosis; ferroptosis; m6A modification
    DOI:  https://doi.org/10.1093/intbio/zyag022
  31. Front Mol Neurosci. 2026 ;19 1892506
    Mitohormesis linking metabolic dysfunction and neurodegeneration: implications for dementia and therapeutic strategies.
    Toshiki Otoda, Hideto Nakajima, Tadateru Takayama.
      Mitochondria are central regulators of cellular metabolism, redox homeostasis, and stress adaptation. Mitohormesis refers to an adaptive response in which mild or transient mitochondrial perturbation activates stress-response pathways that subsequently enhance mitochondrial or cellular resilience; however, persistent or excessive stress can overwhelm adaptive capacity and promote mitochondrial dysfunction and tissue injury. Metabolic diseases, including obesity and type 2 diabetes mellitus, are major risk factors for cognitive decline and dementia, and clinical studies have demonstrated associations between metabolic dysfunction, structural brain abnormalities, accelerated brain aging, and impaired cognitive function. However, direct evidence linking mitochondrial dysfunction to neurodegeneration in humans remains limited, with most mechanistic insights derived from experimental animal models and cultured neuronal systems. Experimental evidence indicates that chronic metabolic stress can disrupt mitochondrial quality control and proteostasis, increase mitochondrial reactive oxygen species production, and promote neuroinflammation and neuronal dysfunction. Conversely, adaptive mitochondrial stress responses can preserve mitochondrial integrity and cellular resilience through coordinated regulation of the integrated stress response, mitochondrial quality-control mechanisms, lysosomal-mitochondrial crosstalk, extracellular vesicle-mediated communication, and inter-organ signaling. In Alzheimer's disease, mitochondrial dysfunction and amyloid-β/tau pathology may interact bidirectionally, potentially generating self-reinforcing cycles of neuronal injury. Lifestyle and pharmacological interventions-including exercise; caloric restriction; nutritional ketosis; and the use of metformin, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists-have been associated with adaptive mitochondrial and metabolic responses involving AMP-activated protein kinase, nuclear factor erythroid 2-related factor 2, mitochondrial biogenesis, mitophagy, and redox signaling. However, evidence that mitohormesis directly mediates their beneficial effects varies substantially across interventions and remains predominantly indirect or hypothesized in humans. Moreover, the discrepancy between encouraging preclinical findings and clinical outcomes highlights important translational barriers, including the lack of validated biomarkers, uncertainty regarding optimal stress intensity and timing, and tissue- and disease-specific differences in adaptive capacity. Collectively, current evidence supports mitohormesis as a conceptual framework for integrating mitochondrial stress adaptation, metabolic dysfunction, and neuronal resilience rather than as an established unifying mechanism underlying neurodegeneration. Defining the conditions under which mitochondrial stress is adaptive, identifying reliable biomarkers of mitohormesis, and determining whether these responses can be safely and effectively modulated in humans will be essential for establishing its therapeutic relevance in metabolic and neurodegenerative diseases.
    Keywords:  dementia; metabolic disease; mitochondrial dysfunction; mitochondrial quality control; mitohormesis; neurodegeneration; oxidative stress; redox signaling
    DOI:  https://doi.org/10.3389/fnmol.2026.1892506
  32. bioRxiv. 2026 Sep 23. pii: 2026.09.22.752907. [Epub ahead of print]
    Integrated stress response activation in combination PG3 and cisplatin-treated TP53 -mutated head and neck squamous carcinoma cells induces potent apoptotic response.
    Xiaobing Tian, Praveen R Srinivasan, Wafik S El-Deiry.
      Cisplatin remains as standard chemotherapy for patients with HNSCC, but rapid development of drug resistance has limited patient benefit. The p53 tumor suppressor plays a central role in the cellular response to DNA damage in cancer, triggering apoptosis to prevent propagation of damaged cells in tumor development. TP53 gene mutations occur in 65-86% of HNSCC. Small molecule PG3 induces the integrated stress response (ISR), leading to apoptosis via the HRI-eIF2α-ATF4-PUMA axis. We hypothesized that a combination of PG3 plus cisplatin could increase apoptosis in TP53 -mutated HNSCC cells through enhanced induction of the ISR and ATF4. PG3 synergized with cisplatin to inhibit cell viability, leading to potent apoptosis in TP53 -deficient cells. The effect was regulated through the HRI-ATF4-NOXA pathway. Furthermore, we identified that cisplatin activates HRI and leads to the degradation of CReP (constitutive repressor of eIF2α phosphorylation) via E3 ligase β-TrCP, contributing to the induction of the ISR. We noted decreased ATF4 levels after treatment with cisplatin, CPT, or PG3 and cisplatin. Thus, combined therapy of PG3 plus cisplatin likely results in adaptation and acquired resistance via degradation of ATF4. We targeted the degradation mechanism of ATF4 by inhibiting β-TrCP1, CK1δ, or CK2, respectively. Each approach successfully blocked ATF4 degradation induced by cisplatin or PG3 plus cisplatin and enhanced apoptosis. Our results provide a rational strategy for triple treatments, involving an ISR inducer, a DNA damaging drug, and a β-TrCP inhibitor/CK1δ inhibitor/CK2 inhibitor, to achieve potent and prolonged anti-tumor effects and overcome chemoresistance in HNSCC.
    DOI:  https://doi.org/10.64898/2026.09.22.752907
  33. Nat Commun. 2026 Sep 28. pii: 10029. [Epub ahead of print]17(1):
    Recoding by N1-methylpseudouridine guides rational mRNA vaccine design.
    Panagiotis Poulis, Giovanni Robecchi, Arina O Kurochkina, Michele Felletti, Marina V Rodnina.
      N1-methylpseudouridine (m1Ψ) is a key modification used in SARS-CoV-2 mRNA vaccines that reduces immunogenicity and increases mRNA stability. Recent studies suggested that m1Ψ can promote ribosomal frameshifting, a translational error generating aberrant peptides that elicit immune responses, raising concerns about unintended antigenicity. Here, we systematically examined the efficiency of frameshifting induced by m1Ψ and the underlying mechanism, aiming to inform future mRNA vaccine design. Using mRNA-based dual-fluorescence reporters in cells, fully in vitro reconstituted translation system, and single-molecule FRET microscopy, we show that m1Ψ increases +1 frameshifting on UUUC motifs in therapeutic mRNAs. Frameshifting occurs when the peptidyl-tRNA pauses in the ribosomal P site, where m1Ψ both weakens codon-anticodon interactions and promotes a frameshifting-prone tRNA conformation. Replacing slippery UUUC motifs with UUCC or UUUU eliminates this effect. Our results reveal how a clinically relevant mRNA modification promotes recoding and show that codon optimization mitigates this risk in therapeutic mRNA design.
    DOI:  https://doi.org/10.1038/s41467-026-77796-3
  34. Wiley Interdiscip Rev RNA. 2026 Sep-Oct;17(5):17(5): e70061
    RNA-Protein Assemblies: A Review of Biophysical Principles and Coarse-Grained Modeling Approaches.
    Muhammad Waleed Iqbal, Patrick R Onck.
      RNA-protein assemblies are fundamental organizers of eukaryotic cell biology, participating in diverse processes such as ribosome biogenesis in nucleoli, mRNA sequestration in nuclear speckles, and genome packaging in viral ribonucleoprotein (vRNP) complexes. Across these systems, multivalent RNA-protein interactions promote self-organization, contributing directly to liquid-liquid phase separation (LLPS) in nucleoli and nuclear speckles, while facilitating assembly and intermediate states in mature structurally organized vRNPs. This review critically examines the molecular grammar underlying these three paradigmatic systems, focusing on how sequence-encoded RNA-IDR chemistry determines condensate morphology, compositional selectivity, and material properties. We then evaluate the experimental and computational approaches used to characterize RNA-protein assemblies, with particular focus on coarse-grained (CG) forcefield development across HPS, Mpipi, CALVADOS, and 1BPA families. We also discuss how emerging multi-domain protein (MDP) models and RNA-compatible forcefields are optimizing the predictive accuracy of molecular simulations. Finally, we explore physics-based and data-driven predictors of LLPS, and reiterate the need for a framework that can predict sequence-based heterotypic IDR-RNA co-phase separation.
    Keywords:  RNA‐protein assemblies; nuclear speckles; nucleoli; vRNP
    DOI:  https://doi.org/10.1002/wrna.70061
  35. Compr Rev Food Sci Food Saf. 2026 Nov;25(6): e70665
    Unlocking the Potential of Yeast Protein for Functional Foods: A Multiscale Overview of Bioactivity, Processing, and Application Challenges.
    Qingfang Ying, Qingrong Huang, Zihao Wei.
      Global shifts in protein supply and demand are reshaping food systems toward sustainability and multifunctionality. Benefiting from its microbial biosynthesis advantage, balanced amino acid profile, and tunable molecular structure, yeast protein exhibits distinctive interfacial, colloidal, and bioactive functionalities that differentiate it from other microbial proteins. These support the potential use of yeast protein as a versatile ingredient in the structural and functional design of food systems. Despite increasing research attention, previous reviews have not systematically integrated source variability, extraction and fractionation strategies, processing-induced structural transformations, and interfacial/colloidal behavior with final food functionality. This review addresses these gaps by linking compositional features and multiscale structure-function relationships to emulsifying, foaming, and gelling behaviors across food matrices. However, commercialization is still restricted by compositional heterogeneity, sensory defects, process scalability, and the lack of standardized safety and performance evaluation. This review integrates advances in structural regulation and functional mechanisms to provide a clearer framework for performance optimization and practical translation of yeast protein in food systems.
    Keywords:  bioactive peptides; structural modulation; technological functionality; yeast proteins
    DOI:  https://doi.org/10.1111/1541-4337.70665
  36. Cancer Rep (Hoboken). 2026 Oct;9(10): e70687
    Regulation of ER Stress-Associated Gene Expression by Lifeguard in Human Breast Cancer Cells.
    Inga Nebel, Sarah Strauß, Frederik Schlottmann, Lena Maria Herrmann, Peter M Vogt, Vesna Bucan.
       BACKGROUND: Despite significant advances in breast cancer therapy, resistance to apoptosis remains a major obstacle to successful treatment. Lifeguard (LFG), an antiapoptotic membrane protein, has been implicated in breast cancer progression; however, its role in endoplasmic reticulum (ER) stress-associated molecular responses and apoptosis-related gene regulation remains incompletely understood.
    AIMS: This study aimed to investigate molecular changes associated with LFG-targeted siRNA treatment and reduced LFG mRNA expression in human breast cancer cells.
    METHODS AND RESULTS: The triple-negative breast cancer cell line MDA-MB-231 and the non-tumorigenic mammary epithelial cell line MCF10A were transfected with LFG-specific siRNA. LFG mRNA expression was analyzed by quantitative RT-PCR. Furthermore, ER stress- and apoptosis-related gene expression was examined using an RT2 Profiler PCR Array, and intracellular calcium-associated fluorescence was assessed by fluorescence-based calcium imaging. LFG mRNA expression was markedly reduced following LFG-specific siRNA treatment in MDA-MB-231 cells, whereas a more moderate reduction was observed in MCF10A cells. LFG-targeted siRNA treatment was associated with altered intracellular calcium-associated fluorescence and differential expression of several ER stress- and apoptosis-related genes, including upregulation of CREB3L3, SREBF1, and INHBE, as well as downregulation of EDEM1, HSPA2, and RRM2.
    CONCLUSIONS: These findings demonstrate that LFG-targeted siRNA treatment and reduced LFG mRNA expression are associated with changes in intracellular calcium-related responses and ER stress- and apoptosis-associated gene expression, particularly in MDA-MB-231 cells. Further studies are required to determine the underlying mechanisms and establish the functional role of LFG in these cellular responses.
    Keywords:  Lifeguard; apoptosis; endoplasmic reticulum; gene expression
    DOI:  https://doi.org/10.1002/cnr2.70687
  37. bioRxiv. 2026 Sep 27. pii: 2026.09.22.753482. [Epub ahead of print]
    Integrative Nanopore and Illumina sequencing reveals age-associated tRNA modification and CCA-tail dynamics in yeast.
    Katherine M Brazell, Christopher Prevost, Natalia Zawrotna, Carrie K Smith, Lindsey N Power, Jeffrey S Smith, Zhangli Su.
      Aging is characterized by a progressive loss of proteostasis. Transfer RNAs (tRNAs) are essential regulators of translation, yet their dynamics during aging remain poorly understood due to challenges in sequencing highly modified RNAs. Here we present a benchmarked Nanopore direct RNA sequencing (RNA004 chemistry) resource that profiles the Saccharomyces cerevisiae tRNAome during replicative aging at single-molecule resolution. Using in vitro transcribed tRNA controls, we establish modification detection thresholds and validate key findings with orthogonal Illumina sequencing. While overall tRNA abundance remains largely stable, our resource reveals age-associated terminal A cleavage at the 3' CCA tail of mature tRNAs, targeted T-loop and anticodon modification changes, and single-molecule evidence of modification co-occurrence. This dataset provides a resource for exploring tRNA regulation, translation fidelity, and longevity.
    DOI:  https://doi.org/10.64898/2026.09.22.753482
  38. Front Nutr. 2026 ;13 1915419
    Endoplasmic reticulum stress as a mechanistic link between nutrition and inflammatory bowel disease.
    Merve Seylan, Sule Arslan, Halit Tanju Besler.
      Inflammatory bowel diseases (IBD) are chronic inflammatory disorders that arise from the complex interplay among genetic predisposition, immune dysregulation, environmental factors, and disruption of intestinal epithelial barrier integrity. Increasing evidence suggests that endoplasmic reticulum (ER) stress may represent an important mechanistic pathway in this multifactorial pathogenesis. Experimental evidence indicates that dietary patterns and nutrient-derived factors may modulate ER stress responses. In this review, the role of ER stress in IBD is discussed from a mechanistic perspective, with particular emphasis on the effects of nutrition on ER stress pathways and the relationship between these interactions and IBD pathogenesis. The available findings are evaluated according to whether they derive from direct human IBD studies, experimental colitis models, intestinal cellular systems, or indirect non-intestinal models. Evidence derived predominantly from experimental and non-intestinal metabolic models indicates that high-fat and high-fructose exposures can activate PERK- and IRE1-associated signaling and CHOP-related terminal responses; however, their direct effects on intestinal UPR signaling and epithelial barrier integrity in human IBD have not been established. In contrast, polyunsaturated fatty acids, flavonoids, polyphenols, and certain micronutrients have been reported to modulate selected UPR markers and support cellular adaptation in experimental systems, although differences in dose, bioavailability, and study model limit clinical extrapolation. Collectively, current evidence suggests that ER stress may represent an important mechanistic pathway linking nutrition and intestinal inflammation, although direct causal evidence linking nutritional exposures to mucosal ER stress and clinical outcomes in humans remains limited. Controlled dietary studies incorporating standardized, pathway-specific mucosal biomarkers are required before this mechanistic framework can inform personalized nutritional strategies or ER-stress-targeted interventions.
    Keywords:  endoplasmic reticulum stress; inflammation; inflammatory bowel disease; nutrition; unfolded protein response
    DOI:  https://doi.org/10.3389/fnut.2026.1915419
  39. Adv Biol (Weinh). 2026 Sep;10(9): e70160
    IGF2BP1-Mediated m6A Modification Enhances the Stability of circ_0088302 to Promote Gastric Cancer Progression.
    Jianjie Li, Xiaoxue Xi, Yang Wang, Hua Li.
       BACKGROUND: Circular RNAs (circRNAs) are recognized as critical regulators of gastric cancer (GC) progression. Nevertheless, the biological function of circ_0088302 in gastric cancer and its epitranscriptomic regulatory mechanism remain unclear.
    METHODS: The expression of circ_0088302 was analyzed based on plasma circRNA data from GSE93541 and RT-qPCR, and its subcellular localization was determined by RNA-FISH. Cellular malignant phenotypes were evaluated using CCK-8 assay, colony-formation assay, wound-healing assay, Transwell assay, and flow cytometry. MeRIP-qPCR, RIP, dual-luciferase reporter assay, and actinomycin D assay were performed to assess m6A modification, IGF2BP1 binding, candidate m6A sites, and RNA stability. AVJ16 was used to inhibit IGF2BP1 function.
    RESULTS: circ_0088302 was highly expressed in plasma samples from GC patients and GC cells. Knockdown of circ_0088302 repressed cell viability, colony formation, and migration, and promoted cell apoptosis. circ_0088302 exhibited m6A enrichment and bound to IGF2BP1, and the predicted 292 site was involved in IGF2BP1-dependent regulation. IGF2BP1 knockdown reduced circ_0088302 levels and accelerated its degradation. AVJ16 suppressed the viability of GC cells and abrogated the malignant phenotypes induced by circ_0088302 overexpression.
    CONCLUSION: IGF2BP1 may facilitate the malignant phenotypes of GC cells by maintaining the RNA stability of m6A-modified circ_0088302, suggesting that the IGF2BP1/circ_0088302 axis may represent a potential therapeutic target for GC.
    Keywords:  IGF2BP1; circRNA; circ_0088302; gastric cancer; m6A
    DOI:  https://doi.org/10.1002/adbi.70160
  40. Funct Integr Genomics. 2026 Oct 02. pii: 279. [Epub ahead of print]26(1):
    METTL14-mediated m6A modification of CXCL9 mRNA regulates macrophage CS polarization to suppress OSCC growth and stemness.
    Bo Yang, Feng Liu, Yanfang Qiu, Wenqiong Wu, Hailin Zhang, Haolei Tan, Cuihong Jiang.
      Oral squamous cell carcinoma (OSCC), the most prevalent histological subtype of oral cancer, is characterized by an immunosuppressive tumor microenvironment (TME) predominantly modulated by tumor-associated macrophages (TAMs). The CXCL9/SPP1 ratio (CS ratio) has been validated as a more reliable prognostic biomarker than the conventional M1/M2 classification. Although methyltransferase-like 14 (METTL14) participates in TAM polarization, its specific role in regulating the CS balance in OSCC remains elusive. This investigation elucidates the mechanism by which METTL14 modulates TAM CS polarization and affects OSCC growth and stemness. We utilized single-cell RNA sequencing (scRNA-seq) data for OSCC and normal samples from Gene Expression Omnibus (GEO) to characterize TAM CS polarization and screen critical regulatory molecules. To independently validate the expression of key candidate genes, we additionally analyzed three independent bulk transcriptomics cohorts from GEO, comprising 330 patient tissue samples. A METTL14-overexpressing TAM model was constructed to explore the effects of METTL14 on CS polarization and OSCC growth and stemness. The target gene of METTL14-mediated m6A modification was identified using the RM2Target database and validated by cellular experiments. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an m6A reader protein, mediates the downstream biological effects of this epigenetic modification. Finally, the impact of METTL14-driven TAM CS polarization on OSCC tumor growth and stemness was verified in vitro and in vivo in a macrophage-specific Mettl14 knockout mouse model. scRNA-seq re-analysis uncovered mutually exclusive CXCL9⁺ and SPP1⁺ TAM populations in OSCC. METTL14 was markedly enriched and co-expressed in CXCL9⁺ TAMs, where it showed a negative correlation with cancer stemness pathways. Independent validation in three bulk transcriptomics cohorts (n = 330) confirmed significant differential expression of CXCL9 and METTL14 between OSCC tumor and normal tissues. In vitro, METTL14 overexpression in TAMs promoted CXCL9⁺ TAM generation and suppressed OSCC cell growth and stemness, an effect attributed to METTL14-mediated m6A modification of CXCL9 mRNA, which was recognized and stabilized by the m6A reader protein IGF2BP3. Consistently, in vivo assays using macrophage-specific METTL14-knockout mice revealed that METTL14 knockdown reduced m6A modification levels of CXCL9 mRNA, promoted the polarization of TAMs toward the SPP1⁺ phenotype, and ultimately accelerated OSCC tumor growth and enhanced cancer stemness. Collectively, this study identifies a novel mechanism wherein METTL14 regulates TAM CS polarization by promoting m6A modification of CXCL9 mRNA, thereby driving TAMs towards a CXCL9⁺ phenotype and suppressing OSCC growth and stemness.
    Keywords:  CS polarization; Cancer stemness; METTL14; Oral squamous cell carcinoma; Tumor-associated macrophages
    DOI:  https://doi.org/10.1007/s10142-026-02053-1
  41. bioRxiv. 2026 Aug 24. pii: 2026.08.22.746448. [Epub ahead of print]
    Kinetic Control of Nuclear-encoded Mitochondrial mRNA Localization and Local Translation.
    Surbhi Sharma, Xuemei Wang, Steven Nguyen, Madeline E Rasband, Trinh T Tat, Prabha Chupal, Jen-Yun Chang, Eric L Van Nostrand, Daniel L Kiss, Aidan I Brown, Furqan M Fazal.
      Most biological processes are dynamic, yet experimental methods predominantly rely on steady-state measurements to investigate their underlying mechanisms. RNA localization is a fundamental aspect of eukaryotic cell organization and is dynamically regulated by cells. While extensively studied in specialized cell types for a limited number of candidate RNAs, the general principles governing dynamic RNA localization at a transcriptome-wide scale remain largely unexplored. Existing transcriptome-wide studies provide only a static snapshot of RNAs residing in specific cellular locales, in part due to the limited availability of tools for probing cellular spatial organization at biologically relevant scales. Here, we leverage the high spatial (tens of nanometers) and temporal (minute) resolution of APEX-seq to quantitatively measure the dependence of RNA transport on molecular motors at a transcriptome-wide scale in living cells. We conducted these experiments in the context of the localization of mRNAs to the mitochondria, which are essential for cellular function. Our findings indicate that the majority of nuclear-encoded RNAs encoding mitochondrial proteins localize to the outer mitochondrial membrane (OMM) for local translation. We reveal a crucial role of retrograde dynein-based motor transport in RNA localization, demonstrating that its disruption severely impairs RNA targeting to the OMM. Time-resolved profiling of RNAs at the OMM revealed that localization is an active process, and even a brief disruption of transport for a few minutes results in a dramatic loss of localization. Moreover, we demonstrate that the translation efficiency (TE) of localized RNAs is a critical determinant of RNA localization in the context of motor-driven transport, as RNAs that delocalize following motor-transport perturbations exhibit lower TE. Using our temporal perturbation data, we also developed a spatiotemporal model that utilizes translation kinetics to capture key features of RNA localization dynamics at the OMM. Together, experiments and modeling suggest that the process of local translation at the OMM is kinetically controlled by the cell, and reveal an unappreciated mechanism by which active transport of RNAs enables cells to modulate their translation within minutes through RNA localization control. Our study demonstrates how simultaneously capturing the kinetics of hundreds of transcripts with minute resolution can uncover general principles of cellular and organelle organization. Together, these experiments and modeling reveal how active transport and translation jointly maintain the OMM-localized transcriptome. More broadly, they identify RNA localization to cellular membranes as a rapidly tunable mechanism for controlling local translation, even in non-polarized cells.
    DOI:  https://doi.org/10.64898/2026.08.22.746448
  42. bioRxiv. 2026 Sep 10. pii: 2026.09.08.750226. [Epub ahead of print]
    Full-length transcriptomics and proteomics reveal how genome minimization reshapes gene expression in synthetic bacteria.
    Enguang Fu, Troy Brier, Jay Cournoyer, Sage Glass, Yang-le Gao, Yanbao Yu, Zane R Thornburg, Karrie Goglin, Gavin John, Tiana Mamaghani, Sujata Shivakumar, Abner Apsley, Christopher J Fields, Angad P Mehta, John I Glass, Zaida Luthey-Schulten.
      JCVI-syn1.0 (Syn1.0) and JCVI-syn3A (Syn3A), genetically synthetic and genome-reduced versions of the naturally occurring bacterium Mycoplasma mycoides, are landmark platforms for defining the gene set required for life, yet how their genomes are expressed at the RNA level remains uncharacterized. We combined full-length PacBio and native long-read RNA sequencing with short-read quantification and complementary proteomics to map transcription, RNA processing, and protein abundance in both cells. In Syn1.0, full-length sequencing resolved 459 operons encompassing 911 genes, revealing pervasive RNA processing with a strong 3' bias. Analysis of the division and cell-wall cluster showed how transcriptional context explained the restoration of genes required for normal cell division in Syn3A. Most antisense and intergenic transcription in Syn1.0 reflected low-level transcriptional noise arising from inherited mis-annotation, read-through, and synthetic sequences. Much of that transcription was lost in Syn3A after genome minimization. Reducing the genome unexpectedly altered the expression of several retained genes by deleting promoters, most prominently reducing expression of the nucleoid protein HupA and central-carbon enzymes. Meanwhile, one third of the coding mRNA pool was allocated to a single 21-gene ribosomal-protein operon, while several other ribosomal proteins had reduced transcript abundance, which possibly led to imbalanced ribosome assembly. Expression of RNA polymerase and central-carbon metabolism declined at both mRNA and protein levels whereas RNase Y degradosome abundance increased. These shifts in the synthetic evolution of Syn3A suggest plausible mechanisms for its reduced chromosome contacts and slower growth. Together, these results show that genome minimization alters not only gene content but also the transcriptional context and resource allocation of retained genes. The analysis and visualization that are shared via Jupyter Notebook provide the RNA-level foundation for whole-cell modeling of the minimal cell.
    DOI:  https://doi.org/10.64898/2026.09.08.750226
  43. Cell Mol Life Sci. 2026 Sep 30. pii: 350. [Epub ahead of print]83(1):
    Biphasic SMN condensates safeguard stress-induced cytoplasmic mislocalization of splicing RNPs.
    Yannick L Riedel, Jessica Dressler, Maximilian T Schilling, Oliver J Gruss.
      Biogenesis of UsnRNPs occurs in distinct steps in the nucleus and the cytoplasm. Sequential cytoplasmic actions of CLNS1A in the PRMT5 complex and of the SMN complex assemble the Sm core structure consisting of RNA and proteins. Nuclear SMN, condensed in Cajal Bodies, promotes late maturation steps. Whether cytoplasmic SMN undergoes condensation, and how this contributes to UsnRNP biogenesis or homeostasis, is poorly defined. Here, we show that molecular crowding stress induces rapid, reversible condensation of cytoplasmic SMN into droplets and filamentous assemblies, S-bodies, that sequester mislocalized cytoplasmic UsnRNPs along microtubules. During stress recovery, S-bodies undergo microtubule-dependent reorganization into split SMN-CLNS1A condensates, Janus bodies, that promote clearance of mislocalized UsnRNPs. Strikingly, cellular models of the SMN-associated disease spinal muscular atrophy fail to assemble S-bodies and to clear cytoplasmic UsnRNPs. Our findings identify stress-induced SMN condensation as a mechanism to buffer and resolve cytoplasmic UsnRNP mislocalization and reveal impaired tolerance to molecular crowding as a hallmark of spinal muscular atrophy.
    Keywords:  Microtubules; Spinal muscular atrophy (SMA); Stress; Survival motor neurons (SMN); UsnRNP
    DOI:  https://doi.org/10.1007/s00018-026-06459-9
  44. Genetics. 2026 Sep 29. pii: iyag268. [Epub ahead of print]
    Pumilio and Brain tumor regulate the expression of Smaug during the Drosophila maternal-to-zygotic transition.
    Alexander J Marsolais, Mariana Kekis, Harrison W Smith, Zhuyi Wang, Chalini Weerasooriya, Timothy R Hughes, Howard D Lipshitz, Craig A Smibert.
      During the Drosophila maternal-to-zygotic transition, maternally deposited RNAs are cleared in a temporally controlled manner. The RNA-binding protein Smaug is a major regulator of maternal mRNA decay and its expression at both the RNA and protein level is limited to a narrow temporal window during the MZT. Here we show that the Pumilio RNA-binding protein promotes degradation of smaug mRNA at the end of the MZT through Pumilio-binding cis-elements in the smaug 3´ untranslated region, and that disruption of this regulation leads to ectopic Smaug protein expression beyond its normal developmental window. We further find that another RNA-binding protein, Brain tumor, also contributes to repression of ectopic Smaug expression. Transcriptome-wide analyses of embryos lacking Pumilio reveal that it directly regulates hundreds of maternal mRNAs after zygotic genome activation, with many of these Pumilio targets also regulated by Brain tumor. The ectopic Smaug protein that results from loss of either Pumilio or Brain tumor causes widespread downregulation of mRNAs that contain Smaug-binding sites. Together, these findings define a post-transcriptional regulatory pathway in which Pumilio and Brain tumor ensure orderly progression of the Drosophila maternal-to-zygotic transition by clearing smaug mRNA and preventing ectopic Smaug activity.
    Keywords:   Drosophila embryo; Bard; Brain tumor (BRAT); Pumilio (PUM); RNA-binding protein; Smaug (SMG); mRNA stability; maternal-to-zygotic transition (MZT); post-transcriptional regulation
    DOI:  https://doi.org/10.1093/genetics/iyag268
  45. MedComm (2020). 2026 Oct;7(10): e70949
    Posttranslational Modifications of p62/SQSTM1 in Health and Disease.
    Weikai Wang, Xin Jiang, Runing Qiu, Chandra Sugiarto Wijaya, Miaoqin Chen, Jin Wang, Liyuan Zhu, Hongchuan Jin, Lifeng Feng.
      p62/SQSTM1 is a multifunctional adaptor protein that serves as a central hub integrating cellular stress responses, including selective autophagy, antioxidant defense, metabolism, and immune signaling. Its diverse functions are precisely orchestrated by a complex network of posttranslational modifications (PTMs) that dynamically regulate its conformation, protein interactions, stability, and subcellular localization. This review provides a comprehensive overview of the p62 PTMs landscape, encompassing phosphorylation, ubiquitination, acetylation, methylation, and emerging cysteine-based modifications. We first discuss how these PTMs coordinately maintain cellular homeostasis by fine-tuning autophagic flux, activating antioxidant programs, coordinating nutrient sensing, preserving genomic stability, and regulating immune responses. We then examine how dysregulation of this PTMs network drives pathogenesis in major diseases including cancer, neurodegenerative disorders, metabolic diseases, and infections, with emphasis on context-dependent molecular mechanisms. Furthermore, we summarize current preclinical evidence targeting p62 PTMs. Finally, we emphasize the critical need for advanced technologies to decipher PTMs crosstalk and dynamic regulation, coupled with the development of corresponding therapeutic strategies, to advance precision medicine. Understanding the p62 PTMs code offers promising opportunities for developing novel biomarkers and targeted therapies for human diseases.
    Keywords:  autophagy; disease; homeostasis; p62/SQSTM1; posttranslational modifications; signal transduction; therapeutic target
    DOI:  https://doi.org/10.1002/mco2.70949
  46. Zhonghua Fu Chan Ke Za Zhi. 2026 Sep 25. 61(9): 748-759
    [Inhibition of RBM5 expression by the interaction between hsa_circ_0006200 and EIF4A3 and its impact on cervical cancer progression].
    R Chen, Y Yuan, Z Zhang, N Yang, X Q Cao.
      Objective: To reveal the biological function and potential molecular mechanism of hsa_circ_0006200 in cervical cancer. Methods: Quantitative polymerase chain reaction (qPCR) was utilized to analyze the expression differences of hsa_circ_0006200 in cervical cancer cell lines versus normal cervical epithelial cells. 5-ethynyl-2'-deoxyuridine (EdU) method was applied for cell proliferation assessment, Transwell assays were for the detection of cell migration and invasion. RNA pull down assay and RNA immunoprecipitation (RIP) assay were applied to determine the interplay between hsa_circ_0006200 and eukaryotic translation initiation factor 4A3 (EIF4A3) and the binding between EIF4A3 and RNA binding motif protein 5 (RBM5). Western blot was carried out to determine protein expression levels of EIF4A3 and RBM5 in SiHa and HeLa cells. Results: In contrast to normal cervical epithelial cells, hsa_circ_0006200 expression was markedly upregulated in cervical cancer cell lines (P<0.001). In vitro, overexpression of hsa_circ_0006200 dramatically enhanced the proliferative, migratory and invasive capacities of cervical cancer cells (P<0.001), whereas hsa_circ_0006200 knockdown restrained the proliferation, migration, and invasion of cervical cancer cells (P<0.05). RNA pull down assay showed that hsa_circ_0006200 could bind to EIF4A3 in cervical cancer cells. RIP assay validated the interaction of EIF4A3 with both hsa_circ_0006200 and RBM5. Knockdown of hsa_circ_0006200 observably upregulated RBM5 protein expression in cervical cancer cells, whereas further EIF4A3 overexpression resulted in downregulated RBM5 protein expression (P<0.01). EdU method and Transwell assays demonstrated that RBM5 knockdown weakened the suppressive impacts of downregulating hsa_circ_0006200 on cervical cancer cell proliferation, migration and invasion (P<0.01). Conclusion: hsa_circ_0006200 expression is upregulated in cervical cancer cells, where it drives cancer cell proliferation, as well as migration and invasion, by repressing RBM5 expression through interaction with EIF4A3.
    DOI:  https://doi.org/10.3760/cma.j.cn112141-20260402-00180
  47. Wiley Interdiscip Rev RNA. 2026 Sep-Oct;17(5):17(5): e70057
    Toward Mapping Spatiotemporally Resolved Transcriptomes and RNA-Protein Interactions.
    Antto J Norppa, Minna-Liisa Änkö.
      RNAs navigate highly regulated life cycles that include synthesis, processing, ribonucleoprotein complex formation, localization, and degradation. However, most transcriptome-wide methods capture static, cell-wide averages that obscure the spatiotemporal aspects-where and when-of RNA life. Here we review recent advances that bring spatial and temporal resolution to transcriptome and RNA-protein interaction analyses by labeling RNA either in defined subcellular locales (RNA proximity labeling) or during defined transcriptional time windows to capture the kinetics of RNA synthesis, degradation, and processing (RNA metabolic labeling). We further discuss how RNA labeling approaches can be integrated with RNA-protein interaction mapping, opening new possibilities for studying ribonucleoprotein dynamics in space and time. Finally, we highlight emerging developments and outline future directions for spatiotemporal analysis of the RNA life cycle.
    DOI:  https://doi.org/10.1002/wrna.70057
  48. Redox Biol. 2026 Jul 18. pii: S2213-2317(26)00316-2. [Epub ahead of print]97 104317
    Integrated multi-PTM omics reveals key host pathways in human coronavirus 229E infection.
    Xiaolu Li, Adam Kabza, Matthew J Gaffrey, Madelyn R Berger, Song Feng, Austin Gluth, Marina A Gritsenko, Patricia S Miller, Rosalie K Chu, Doo Nam Kim, Abdullah D Shouaib, Wei-Jun Qian, Katrina M Waters, Amy C Sims, Tong Zhang.
      Viruses manipulate host cellular functions to promote replication and evade antiviral responses, and many processes in host-virus interactions are regulated by protein post-translational modifications (PTMs). While previous studies have examined individual PTMs in host-virus interactions, a comprehensive, multi-PTM perspective of host remodeling during coronavirus infection remains lacking. To address this gap, we applied our multi-PTM omics platform to simultaneously quantify protein abundance, cysteine oxidation, phosphorylation, and lysine acetylation in human lung fibroblasts (MRC5) and epithelial cells (A549) infected with human coronavirus strain 229E (HCoV-229E) at 8, 16, and 24 h post-infection. We observed modest changes in the global host proteome, with only a small fraction of proteins affected even 24 h post-infection. In contrast, host PTM landscapes were rapidly and extensively remodeled, exhibiting pronounced and cell type-specific alterations in redox and phosphorylation states as early as 8 h post-infection. Phosphorylation profiling revealed widespread remodeling of host signaling networks with distinct temporal and directional patterns between MRC5 and A549 cells, while redox profiling uncovered divergent oxidative regulation of proteins involved in infection-related pathways. Notably, a subset of host proteins showed coordinated regulation across multiple PTM types without corresponding changes in abundance, highlighting potential PTM crosstalk during HCoV-229E infection. Among these, heat shock protein 90 beta (HSP90B) displayed dynamic regulation across cysteine oxidation, phosphorylation, and acetylation, and pharmacological inhibition of HSP90B significantly suppressed HCoV-229E replication. Together, these results provide a comprehensive, multi-dimensional view of host PTM remodeling during HCoV-229E infection and demonstrate that integrated multi-PTM omics can reveal functionally relevant host factors and therapeutic vulnerabilities not apparent from protein abundance measurements.
    Keywords:  Acetylation; Coronavirus; Host-directed antiviral targets; Host–virus interactions; Multi-PTM; Multi-PTM omics; Phosphorylation; Post-translational modification; Redox
    DOI:  https://doi.org/10.1016/j.redox.2026.104317
  49. Trends Biochem Sci. 2026 Oct 01. pii: S0968-0004(26)00285-9. [Epub ahead of print]
    Cell-free RNA fragmentomics: rethinking the biology of RNA liquid biopsies.
    Valentina Blanco, Mauricio Castellano, Juan Pablo Tosar.
      Cell-free RNA (cfRNA) is emerging as a promising analyte for liquid biopsy because it captures dynamic changes in gene expression across tissues and disease states. However, interpretation of cfRNA profiles remains limited by the lack of a unifying framework describing how extracellular RNAs are released, processed, and stabilized. Here, we propose that concepts from cell-free DNA fragmentomics provide a useful lens to interpret cfRNA biology and introduce the concept of cfRNA fragmentomics. We argue that many cfRNAs originate as intracellular ribonucleoprotein complexes that undergo extracellular ribonuclease processing, generating stable fragmented RNAs associated with proteins and other carriers. Under this framework, informative cfRNA signatures may arise not only from diseased tissues but also from indirect systemic responses to disease.
    Keywords:  RNA fragmentomics; cancer biomarkers; cfRNA; extracellular RNA
    DOI:  https://doi.org/10.1016/j.tibs.2026.09.007
  50. Front Immunol. 2026 ;17 1935553
    Post-translational modification crosstalk in acute pancreatitis: linking acinar stress to innate immune amplification and tissue repair.
    Mengwei Chen, Peng An, Shenglong Jing, Longlong Wu, Rong Wang.
      Acute pancreatitis (AP) is a sterile inflammatory disease initiated by acinar cell stress and amplified through innate immune, vascular, and inter-organ responses, yet effective disease-modifying therapies remain unavailable. Although premature digestive enzyme activation, organelle stress, sterile inflammation, and microvascular failure are well-recognized features of AP, the mechanisms linking early acinar stress to coordinated injury across epithelial, immune, stromal, and vascular compartments remain insufficiently integrated. Emerging evidence suggests that post-translational modifications (PTMs) constitute a dynamic regulatory layer through which metabolic stress is converted into damage-associated molecular pattern release, innate immune activation, inflammatory cell death, tissue repair, and disease progression. This review examines how metabolic stress remodels lactylation, acetylation, phosphorylation, ubiquitination, and related PTMs in AP and how their functional convergence and selected PTM interactions shape DAMP sensing, inflammasome activation, macrophage reprogramming, neutrophil recruitment and extracellular trap formation, cytokine amplification, mitochondrial dysfunction, apoptosis, pyroptosis, ferroptosis, microvascular barrier failure, and systemic complications. We propose an integrated framework linking acinar stress to PTM remodeling, innate immune amplification, and inflammatory resolution. Across acinar, ductal, immune, stellate, and endothelial compartments, PTMs regulate protein stability, subcellular localization, transcriptional programs, organelle quality control, and intercellular signaling. Selected PTM pathways exhibit stage- and cell-dependent effects; for example, lactate-associated lactylation may exacerbate early ferroptotic injury while promoting reparative macrophage polarization during recovery. This framework positions PTM remodeling as a context-dependent immunometabolic control system while recognizing that direct molecular PTM-PTM crosstalk remains incompletely demonstrated in AP.
    Keywords:  acute pancreatitis; immunometabolism; innate immunity; macrophage polarization; neutrophil extracellular traps; post-translational modifications; sterile inflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1935553
  51. Nat Commun. 2026 08 31. pii: 10345. [Epub ahead of print]17(1):
    RBP-Driven RNA sorting and local translation establish the molecular identities of individual sensory axons.
    Elizabeth S Silagi, Ezechukwu Nduka, Jesus Zuniga Paiz, Maria F Pazyra-Murphy, Shamsuddin A Bhuiyan, William Renthal, Rosalind A Segal.
      Neurons extend long axons that traverse distinct microenvironments, yet how these subcellular compartments acquire and maintain specialized identities remains unclear. Here, we use spatial translatomics to define the local translatomes of somatosensory dorsal root ganglion (DRG) neurons. Translating Ribosome Affinity Purification and RNA sequencing (TRAP-seq) reveal thousands of mRNAs preferentially translated within central axons, peripheral axons, or DRG somata, establishing compartment-specific translational programs. Many of these transcripts encode ion channels and neurotransmitter receptors that may confer distinct electrophysiological and regenerative properties to each axon. Integration of the TRAP-seq data with published RNA-seq identify locally translated components that change following neuropathic injury and could thereby adjust neuronal activity. We identify RNA regulons coordinated by RNA-binding proteins (RBPs) SFPQ and SRSF10, which preferentially bind and traffic mRNAs to peripheral or central axons, respectively. These findings indicate that RBP-guided RNA sorting and local translation enable the establishment and dynamic local modulation of somatosensory function.
    DOI:  https://doi.org/10.1038/s41467-026-77192-x
  52. Plant Cell Environ. 2026 Sep 29.
    Mechanisms of Plant Responses to Waterlogging-Induced Hypoxia: Integrated Regulatory Reprogramming for Survival and Recovery.
    Xinyue Jiang, Yaseen Khan, Ling-Feng Miao, Fan Yang.
      Waterlogging is a serious abiotic stress caused by climate change that negatively affects plant growth and productivity. In response to waterlogging, plants activate a coordinated series of physiological, metabolic and molecular adjustments that maintain cellular homoeostasis and support survival. This review synthesises recent advances in the mechanisms by which waterlogging-induced oxygen deprivation is sensed and transduced into coordinated molecular programmes that determine plant survival and stress recovery. Particular attention is given to oxygen-sensing hubs centred on ethylene response factor group VII, which are regulated by the N-end rule/N-degron pathway and activate downstream stress-response programmes. Additionally, metabolic reprogramming under hypoxia, including the shift from aerobic respiration to anaerobic pathways (e.g., lactate and ethanolic fermentation) that sustain ATP production, is further examined. Furthermore, redox regulation during hypoxia-reoxygenation is discussed, highlighting the dynamics of reactive oxygen species, antioxidant defences, heat shock protein networks, and proteostasis mechanisms that constrain metabolic flux. Moreover, hormone-mediated growth-survival decisions, contrasting adaptive strategies, such as gibberellic acid-DELLA-mediated growth restraint and ethylene-driven gibberellic acid-abscisic acid signalling, are discussed. Building on this foundation, we present an integrative framework linking these regulatory layers into a coordinated system and compare its deployment across species to explain divergent tolerance outcomes. Finally, we translate these mechanisms into applied crop improvement, addressing breeding targets, ideotype design and field management, and identify key regulatory nodes and priority directions for advancing waterlogging tolerance.
    Keywords:  core pathways; energy strategies; hormonal crosstalk; hypoxia signalling; redox regulation; tolerance‐recovery; waterlogging stress
    DOI:  https://doi.org/10.1111/pce.70941
  53. Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250279. [Epub ahead of print]381(1960):
    Protein rheostasis: quality control in metastable proteomes.
    Michele Vendruscolo.
      Protein homeostasis is often described as the capacity of cellular quality-control systems to maintain proteome function by favouring functional protein states. Yet many proteins can populate multiple states, including native conformations, liquid-like condensed assemblies, and aggregated states, reflecting the metastability of the proteome. As a framework for understanding how cells preserve proteome function under such conditions, we discuss protein rheostasis as the system that regulates thermodynamic driving forces and kinetic barriers to control the flux between alternative states over time. Framing proteome maintenance in terms of rheostatic control over the multiple states helps rationalize how ageing, stress, and mutations redistribute populations towards condensed and aggregated states by eroding kinetic buffering capacity, and it suggests therapeutic opportunities that restore control by tuning the transitions between metastable states. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.
    Keywords:  liquid–liquid phase separation; protein aggregation; protein homeostasis; protein misfolding
    DOI:  https://doi.org/10.1098/rstb.2025.0279
  54. PLoS One. 2026 ;21(10): e0359197
    Intronic RNA of yeast RPL22 paralogs acts as an allosteric switch.
    Kateřina Abrhámová, Alexandra Gredová, Karolína Navrátilová, Mohamed Boumaiza, Petr Folk.
      Ribosomal proteins, because of their RNA-binding capacity, may engage various cellular RNAs and fulfill non-ribosomal roles. Previously, we and others described the intergenic regulation mediated by splicing of RPL22 paralogs in Saccharomyces cerevisiae. Here, we prepared a panel of RPL22A/B intronic mutants with respect to their RNAfold-predicted features and analyzed their properties. We tested splicing efficiency and Rpl22-intron binding using an intron-containing reporter and a yeast three-hybrid system, respectively. We found that the splicing of RPL22 introns can be inhibited by stabilizing a predicted stem as part of a particular type of conformation (I structure). Stabilizing the formation of an alternate stem (P structure) permitted splicing. Binding of the Rpl22 protein to the intron led to enhanced splicing inhibition in WT and several of the mutants, which we interpret as stabilization of the I structure. Mutagenesis identified both the main and alternative 5'ss and additional stem loops as part of the regulatory mechanism. The inhibitory conformation of the intron did not prevent recognition of the 5'ss and branch point, but rather stalled splicing at a later stage, before the first catalytic step. We conclude that the structural ensemble of the RPL22 pre-mRNA behaves as an allosteric switch that responds to Rpl22 concentration.
    DOI:  https://doi.org/10.1371/journal.pone.0359197
  55. Aging Dis. 2026 Sep 09.
    Ubiquitin-Dependent Protein Quality Control in Polyglutamine Diseases.
    Matthew V Prifti, Kristin Richardson, Sokol V Todi.
      Polyglutamine diseases comprise a family of nine age-dependent disorders caused by CAG triplet-repeat expansions that produce misfolded proteins with elongated glutamine tracts. Although these diseases share proteotoxic stress and engagement of protein quality control pathways as responses to their presence and disruptive activities, they differ in protein context, normal function, localization, interactomes and selective vulnerability. Here, we review how expanded polyglutamine proteins engage ubiquitin-dependent protein quality control across Huntington's disease, dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy, and spinocerebellar ataxias 1, 2, 3, 6, 7 and 17. Rather than treating protein quality control as a uniform response, we emphasize pathway selectivity. A central theme arises across these diseases: mutant polyglutamine proteins are recognized by ubiquitin-related machinery, but recognition does not necessarily produce productive degradation. Instead, disease-specific outcomes are shaped by tissue context, subcellular localization, aggregate state, disease protein fragmentation, normal protein function, compensatory pathway activation and local proteostasis capacity over time. The information synthesized in this review may help the field develop a more comparative and granular understanding of processes and pathways that are shared or divergent among polyglutamine diseases and may also inform more targeted therapeutic strategies for this family of incurable disorders.
    DOI:  https://doi.org/10.14336/AD.2026.0887
  56. Toxicol Sci. 2026 Sep 29. pii: kfag129. [Epub ahead of print]
    Endothelial Proteotoxic Stress Drives Inhaled Benzene-Induced Vascular Inflammation in Mice.
    Samantha A McFall, Marina V Malovichko, Nalinie S Wickramasinghe, Breandon S Taylor, Mohammad T Malik, Daniel J Conklin, Igor N Zelko, Sanjay Srivastava.
      Benzene exposure is associated with increased cardiovascular disease (CVD) risk, yet the mechanisms linking benzene to vascular injury remain incompletely understood. Here, we investigated the effects of benzene and its reactive metabolite trans,trans-muconaldehyde (MA) on endothelial activation and leukocyte recruitment, early events in atherogenesis. Wild-type and endothelial-specific heat shock protein A1B overexpressing (EC-HSPA1B-TG) mice were exposed to inhaled benzene (1 ppm), and leukocyte dynamics were assessed by intravital microscopy. Complementary studies in vitro examined MA-induced endothelial activation via leukocyte adhesion assays, RNA sequencing, pharmacological interventions, and siRNA-mediated gene silencing. Benzene inhalation increased leukocyte rolling (16-21-fold) and adhesion (11-44-fold) in vivo with female mice exhibiting greater responses than males. In vitro, MA enhanced monocyte adhesion (1.7-fold) and transmigration (1.4-fold) and induced a conserved transcriptional program characterized by activation of oxidative stress, unfolded protein response (UPR), MAPK signaling, and heat shock pathways. MA stimulated phosphorylation of p38, JNK, and eIF2α, increased XBP1 splicing, elevated reactive oxygen species generation, and depleted glutathione. Alleviation of ER stress with 4-phenylbutyric acid attenuated MA-induced expression of HSPA1B, ATF3, and ICAM1. Conversely, HSPA1B silencing exacerbated endothelial activation and stress signaling, whereas endothelial-specific overexpression of HSPA1B significantly reduced benzene-induced leukocyte recruitment in vivo. Collectively, these findings identify proteotoxic stress as a central mechanism of benzene-induced vascular toxicity. Further, we demonstrate that activation of the heat shock pathway (HSF1-HSPA1B) serves as a protective response that limits endothelial inflammation. These results provide new mechanistic insight into how environmental benzene exposure may promote vascular injury and CVD in humans.
    Keywords:  Benzene; cardiovascular disease (CVD); endothelial activations; heat shock protein; muconaldehyde; volatile organic compounds (VOCs)
    DOI:  https://doi.org/10.1093/toxsci/kfag129
  57. EMBO Rep. 2026 Sep 30.
    FBXL21 regulates diurnal proteostasis in skeletal muscle by targeting DNAJB6 and client proteins.
    Ji Ye Lim, Jaebok Wi, Marvin Wirianto, Chorong Han, Sun Young Kim, Jane Nguyen, Sehyun Jung, Kristin Eckel-Mahan, Sung Yun Jung, Karyn A Esser, Zheng Chen, Seung-Hee Yoo.
      Circadian regulation of proteostasis, a key determinant of muscle health, remains poorly understood. Here, we identify DNAJB6, an Hsp40 (DnaJ) co-chaperone, as a substrate of the circadian E3 ligase FBXL21. FBXL21 mediates the ubiquitination-dependent proteasomal degradation of both DNAJB6 and its client proteins, including Desmin. In contrast, myopathy-causing mutations of DNAJB6 confer resistance to FBXL21-directed degradation. Fbxl21 KO C2C12 cells display aberrant Desmin accumulation, and show aggravated cytoplasmic accumulation of TDP-43, another DNAJB6 client protein, in response to heat shock. Under timed exercise as a physiological stressor, WT mice display robust diurnal rhythms in the levels of stress granule markers (G3BP1 and FUS) and TDP-43 as a function of exercise timing. In contrast, the Fbxl21 hypomorph Psttm mutant mice show elevated expression of these proteins without exercise, which is exacerbated under exercise-induced stress conditions. Importantly, these abnormalities are rescued by skeletal muscle-specific FBXL21 expression. Our study elucidates a novel diurnal regulatory mechanism of skeletal muscle proteostasis via FBXL21 as a chaperone-linked E3 ligase, highlighting the FBXL21-DNAJB6 axis as a potential therapeutic target for myopathies.
    DOI:  https://doi.org/10.1038/s44319-026-00922-1
  58. Front Mol Biosci. 2026 ;13 1939425
    The mitochondrial DNA-cGAS-STING axis in colorectal cancer: a focused review of context-dependent roles and therapeutic opportunities.
    Huayang Gui, Yali Zhang, Xingxing Yuan.
      Immune checkpoint blockade produces durable benefit mainly in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC), whereas most microsatellite-stable/mismatch repair-proficient (MSS/pMMR) tumors remain poorly inflamed and resistant to immunotherapy. This focused narrative review examines how mitochondrial DNA (mtDNA)-derived danger signals engage the cGAS-STING pathway in CRC, distinguishes canonical DNA sensing from noncanonical STING activation and STING-independent cGAS functions, and evaluates therapeutic strategies that modulate this axis. We qualitatively synthesize peer-reviewed mechanistic and translational studies addressing mtDNA release, pathway routing, cellular context, therapeutic targeting, and biomarkers in CRC, while drawing on pan-cancer and DNA-damage studies only when they clarify pathway architecture or translational constraints. No new experimental, patient-level, or case-series data are presented. Current evidence indicates that biological outcome depends on more than pathway activation alone. Signal amplitude and duration, STING trafficking and proteostasis, downstream IRF3- versus NF-κB-biased signaling, autophagy and mitophagy, metabolic state, pathway abundance, and responding cell type collectively determine whether activation supports antitumor immunity or chronic inflammation and immune suppression. Nuclear DNA damage can also activate noncanonical STING programs independently of cGAS, whereas cGAS can exert STING-independent functions. Upstream mtDNA-origin interventions may provide a more localized route to pathway activation by exploiting tumor mitochondrial stress, but cGAS is not intrinsically mtDNA-specific and any safety advantage over direct STING agonism remains unproven clinically. Clinical translation should therefore prioritize origin-resolved biomarkers, cell-specific pharmacodynamic readouts, tumor-localized and transient pathway modulation, and biomarker-stratified trials.
    Keywords:  cGAS-STING; colorectal cancer; immunotherapy; innate immunity; mitochondrial DNA; mitochondrial stress; tumor microenvironment
    DOI:  https://doi.org/10.3389/fmolb.2026.1939425
  59. Cell Death Discov. 2026 Sep 30. pii: 389. [Epub ahead of print]12(1):
    JP-1302 inhibits RNA polymerase I transcription and induces nucleolar stress in cancer cell lines.
    Sheetanshu Saproo, Styliani Papadaki, Johana Fernandez-Martinez, Pinky Sultana, Dimitris C Kanellis, Jiri Bartek, Mikael S Lindström.
      Cancer cells upregulate ribosomal RNA (rRNA) synthesis to sustain the elevated ribosome production that fuels rapid proliferation, creating a dependency that renders RNA polymerase I (Pol I) transcription a pharmacological vulnerability. JP-1302 is a blood-brain barrier-penetrant 9-anilinoacridine derivative developed as an α2C-adrenergic receptor antagonist, but also recently identified as an RNA Pol II inhibitor at micromolar concentrations (~5-10 μM). Here we show that JP-1302 also suppresses Pol I-driven 47S pre-rRNA synthesis at submicromolar-to-low-micromolar concentrations, evidenced by loss of nascent EU-labelled rRNA and reduced activity of an rDNA promoter-driven luciferase reporter. This was accompanied by preferential proteasome-dependent degradation of the Pol I catalytic subunit POLR1A, independent of α2C-adrenergic receptor signalling, displacement of POLR1A from the rDNA promoter and progressive disruption of nucleolar morphology. Growth inhibitory IC50 values across a panel of normal and cancer cell lines, including glioblastoma, ranged from submicromolar to low micromolar. Nucleolar stress stabilised p53 and induced p21 expression at low-to-intermediate concentrations, without evidence of DNA damage at these doses (no γH2AX increase at concentrations sufficient to abrogate Pol I transcription). Interestingly, p53-null and p53-wild type cells showed comparable S-phase depletion in response to JP-1302. At higher concentrations, JP-1302 additionally caused covalent trapping of TOP2A/TOP2B, accompanied by delayed γH2AX induction, and enrichment of the FACT subunits SSRP1 and SPT16 on chromatin. Together, these findings identify JP-1302 as a pharmacologically distinct inhibitor of ribosome biogenesis with broader, dose-dependent chromatin-disruptive activity.
    DOI:  https://doi.org/10.1038/s41420-026-03381-8
  60. Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2615985123
    Dynamic tRNA modification programs align codon usage with growth-phase-specific gene expression in Pseudomonas aeruginosa.
    Yannick Noah Frommeyer, Jingjing Sun, Junzhou Wu, Benedikt Kennepohl, Julius Witte, Nicolas Oswaldo Gomez, Jana Battermann, Leon Becker, Pierina Cetraro, Ruth Verstraten, Jürgen Tomasch, Andreas Pich, Daniel P Depledge, Peter C Dedon, Susanne Häussler.
      Post-transcriptional transfer RNA (tRNA) modifications dynamically regulate translational capacity, yet whether the tRNA epitranscriptome is temporally coordinated with gene expression programs during bacterial growth remains unknown. Here, we combine time-resolved nanopore tRNA sequencing, liquid chromatography-tandem mass spectrometry modification profiling, transcriptomics, and proteomics across the Pseudomonas aeruginosa PA14 growth cycle to show that tRNA-modifying enzymes, the corresponding tRNA modifications, and modification-dependent genes are expressed in a coordinated temporal cascade. GidA-dependent 5-methylaminomethyl-2-thiouridine (mnm5s2U) modifications exemplify this program: GidA expression peaks during early growth, followed by rising mnm5s2U levels coinciding with maximal expression of genes enriched in rare AGA and UUA codons, with a concomitant enrichment of virulence-associated functions. This sequential pattern is consistent with a feedforward architecture in which the modification machinery acts in advance of translational demands. This mechanism is especially relevant for a set of horizontally acquired genes, suggesting that temporally programmed tRNA epitranscriptomic remodeling may help bridge local codon usage deviations between horizontally acquired genes and the core translational context.
    Keywords:  bacterial infection; epitranscriptomics; systems biology; tRNA
    DOI:  https://doi.org/10.1073/pnas.2615985123
  61. Biochem Pharmacol. 2026 Sep 30. pii: S0006-2952(26)00850-6. [Epub ahead of print] 118508
    Pharmacological translation of cancer missense mutations for therapeutic targeting with small molecules.
    Mariam Fouad.
      Targeted therapies built around specific genetic driver mutations have become a cornerstone of precision oncology. These mutations, often found in oncogenes such as Kirsten rat sarcoma (KRAS) or tumor suppressors such as TP53, contribute to tumor initiation, progression, and therapeutic resistance. Recent successes with KRAS inhibitors targeting G12C and G12D mutations highlight the clinical potential of mutation-specific drug design. Concurrently, advances in machine learning have enhanced predictions of missense variant effects by integrating amino acid dynamics, structural perturbations, and pathogenicity scores. This review synthesizes current computational tools and emerging therapeutic small-molecule inhibitors, protein degraders, and proximity-based therapeutics to provide a comprehensive framework that links structure-function relationships to the rational design of next-generation cancer treatments.
    Keywords:  Amino acid substitution; Computational prediction; Secondary mutation; Structure conformation; Structure–activity relationship; Tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1016/j.bcp.2026.118508
  62. Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2613911123
    Thermosensor OsTT3.1 enhances rice thermotolerance by degrading OsGSK2 to reduce OsHsfB2c phosphorylation and nuclear translocation.
    Jiaqi Hou, Jin Yang, Tingyu Chen, Yating Zhao, Daoyi Tu, Zetian Guo, Mutian Yang, Ziyi Wang, Yan Zeng, Nachuan Zhang, Lijia Li.
      Heat stress significantly impacts rice productivity, making understanding of molecular mechanisms crucial for crop improvement. Here, we report a regulatory pathway in rice that integrates a membrane-localized E3 ubiquitin ligase (OsTT3.1), glycogen synthase kinase 2 (OsGSK2), and the heat shock factor B2c (OsHsfB2c) to modulate thermotolerance. We demonstrate that OsGSK2 directly interacts with and phosphorylates OsHsfB2c both in vitro and in vivo, a modification that promotes its nuclear translocation. Functional analyses revealed that mutations in both OsGSK2 and OsHsfB2c enhance heat tolerance, while their overexpression reduces thermotolerance. Furthermore, we identified OsTT3.1 as an OsGSK2-interacting protein that promotes OsGSK2 degradation through ubiquitin-mediated proteolysis. Double mutant analysis (ostt3.1/osgsk2) showed increased heat tolerance compared to ostt3.1 single mutants, confirming that OsTT3.1 acts upstream of OsGSK2. Transcriptomic profiling of oshsfb2c mutants under normal and heat stress conditions uncovers widespread dysregulation of genes involved in primary metabolism and stress defense, indicating that OsHsfB2c functions as a transcriptional repressor of heat-responsive pathways. Our findings establish a sophisticated regulatory cascade where OsTT3.1-mediated degradation of OsGSK2 relieves the phosphorylation of OsHsfB2c, thereby derepressing heat stress responses and enhancing thermotolerance in rice. This "brake-release" mechanism serves as a critical buffering system that allows rapid attenuation of the OsGSK2-OsHsfB2c repressive module under heat stress, ensuring timely and robust activation of stress responses and optimal metabolic reprogramming.
    Keywords:  heat stress; nuclear translocation; phosphorylation; rice; ubiquitin-mediated degradation
    DOI:  https://doi.org/10.1073/pnas.2613911123
  63. bioRxiv. 2026 Sep 08. pii: 2026.09.04.749507. [Epub ahead of print]
    Ebola virus mRNAs contain RNA structures that are critical for viral infection and targetable by antisense oligonucleotides.
    Michelle Luo, Judith Olejnik, Kristina Meier, Tanja Hann, Elke Mühlberger, Anna Marie Pyle.
      Filoviruses, such as Ebola virus (EBOV), are highly pathogenic non-segmented negative-sense RNA viruses (nsNSVs) with limited therapeutic options. Filovirus RNA structures remain largely untapped due to the enhanced biosafety requirements for handling infectious virus. Here, we present the first in-cell secondary structure maps of four EBOV mRNAs (VP35, VP40, VP30, and VP24) using two orthogonal chemical probing approaches: SHAPE-MaP and fbDMS-MaP. We find that EBOV mRNA coding sequences (CDS) are highly structured, much like +ssRNA viruses, whereas untranslated regions (UTRs) are significantly less structured. This suggests that high CDS structure contents are general features of viral translation templates, and that nsNSVs have evolved separate regulatory function at the RNA structure level that extends beyond using distinct mRNAs and genomes. These structure maps are consistent with formation of mRNA 5' hairpin structures during infection and reveal numerous additional RNA structures within the CDS, 3' UTRs, and at CDS-UTR junctions. To assess functionality, we disrupted these structures with locked nucleic acid (LNA) antisense oligonucleotides. Disrupting the TSS hairpins in VP35, VP30, and VP24 decreased infection by >60%, indicating these mRNA structures are critical for infection. LNA targeting of the newly identified structures reduced EBOV infection by 31% to 88%, thereby linking RNA structural integrity to viral function. Synonymous mutation rates and covariation analysis provided evolutionary support across mammalian filoviruses for the functional RNA elements observed. Collectively, these results demonstrate EBOV mRNAs contain numerous conserved RNA motifs contributing to viral infection, and that these elements represent promising targets for development of pan-filoviral therapeutics.
    Importance: EBOV and related filoviruses pose a significant global health threat, yet our understanding of the RNA architectural mechanisms driving infection remains incomplete. Due to enhanced biosafety constraints, filovirus RNA structures have not been mapped in cells. Here, we experimentally map secondary structures of four EBOV mRNAs at biosafety level 4. We find that structure content is concentrated within protein coding regions, resembling the highly structured genomes of positive-sense RNA viruses, while untranslated regions are relatively unstructured. This separation of relative structural content reflects how translation and replication are delegated between mRNAs and genomes in negative-sense RNA viruses. We also show that these structures are critical for infection, with disruption reducing infection more than 80% in liver cells. Evolutionary analyses suggest a set of these regulatory elements are conserved across mammalian filoviruses. Broadly, this work expands the repertoire of filovirus regulatory elements, revealing new potential targets for developing pan-filoviral therapeutics.
    DOI:  https://doi.org/10.64898/2026.09.04.749507
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