bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–08–23
sixty papers selected by
Cédric Chaveroux, CNRS
  1. Yeast Rai1p and the RAC complex (Ssz1p/Zuo1p) modulate uORF-mediated GCN4 translational control under stress conditions.
  2. Codon optimality modulates cellular stress and innate immune responses triggered by exogenous RNAs.
  3. Anticodon nucleotide modifications affect translational tuning by the ribosomal CAR surface.
  4. Single-Molecule Imaging Reveals ERK-Dependent Spatial Translation in Cardiomyocytes.
  5. Astrocytes instructively regulate neuronal translation.
  6. Loss of O-GlcNAc Transferase activity impairs the dynamic formation of protective stress granules in ischemic cardiomyocytes.
  7. Poly(A)-binding proteins in trypanosomatids and Plasmodium.
  8. The assembly factors Rei1 and Reh1 share a redundant function in loading ribosomal protein eL24.
  9. Targeting CPSF73, the mRNA 3' end processing endonuclease, moves cancer cells away from the mesenchymal state.
  10. Unmasking the modified small non-coding RNome: detection strategies for RNA modifications.
  11. A Revised Ribosome-Antibiotic Model with Proportional Feedback Synthesis Explains Recovery from Translation Inhibition.
  12. Chaperone condensates buffer the heat shock response against pleiotropic inputs.
  13. Bacterial small regulatory RNAs.
  14. mRNA translational dynamics mediates totipotent-like reprogramming.
  15. The hypusine circuit: eIF5A at the crossroads of polyamine metabolism, malignant progression, and therapeutic vulnerability.
  16. Transcriptome-wide splicing analysis reveals HuR-regulated post-transcriptional programs in osteocytes.
  17. The methyltransferase Rrp8 is a positive regulator of autophagy flux in Saccharomyces cerevisiae.
  18. Chronic stress disrupts the network among stress granules, P-bodies, and motor proteins.
  19. BAG6-RNF115 Couples Protein Quality Control with Ribosome Assembly.
  20. RPL41 stabilizes ribosome dynamics and supports long-protein homeostasis in mammals.
  21. Competing Molecular Interactions Govern the Dynamical Arrest of G3BP1 Condensates.
  22. Selenoprotein S associates with complexes governing membrane protein biogenesis and translation-associated processes.
  23. Focus on DnaJ protein research from Arabidopsis to crop improvement.
  24. YTHDF3-Dependent m6A Modification of cGAS Drives Nanoparticle-Induced Senescence in Spermatocytes.
  25. Human Hsp70 paralogs display selective J-domain interactions tuning proteostasis under stress.
  26. The lncRNA PHAROH augments MYC mRNA levels in insulin-producing cells by counteracting TIA1-induced MYC silencing.
  27. A formyl axis links metabolism to translation.
  28. Interplay between stress granule-like structures and nuclear RNA export in a heat shock-specific manner.
  29. N-Acetyltransferase 10 (NAT10) at the crossroads of metabolism, immunology, and cancer biology.
  30. Measuring Live-Cell mRNA Translational Dynamics with Split Luminescent Tagging in HEK293 Cells.
  31. Exercise as a Programmable Regulator of Mitophagy Sensitivity in Aging Muscle and Age-Related Disease.
  32. Guardians of splicing: quality control mechanisms of snRNA variants.
  33. Deubiquitylase OTUD3 regulates integrated stress response to suppress progression and sorafenib resistance of liver cancer.
  34. Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
  35. N6-methyladenosine (m6A) RNA methylation in poultry growth, reproduction, metabolism, and disease: a review.
  36. Antisense oligonucleotide-mediated disruption of mRNA localisation inhibits angiogenesis.
  37. Haikun Shenxi Capsule Alleviates Renal Fibrosis in CKD Mice by Targeting the METTL3/IGF2BP3-Mediated m6A Modification of NKD2.
  38. Epitranscriptomic regulation of host-virus interactions.
  39. Shaping Spliceosome Dynamics Through Protein Arginine Methylation.
  40. ALKBH3 is an NPM1-dependent nucleolar protein required for rRNA biogenesis and translation.
  41. EOLA1 functions in nucleotide salvage through deacetylating free N4-acetylcytidine.
  42. Global transcriptomic response of Malassezia pachydermatis isolates under ketoconazole-induced stress.
  43. Biomolecular condensates as dynamic regulators of musculoskeletal homeostasis, disease, and therapeutic challenges.
  44. Subcellularly Resolved 3D Translatome in Mouse Oocytes and Early Embryos.
  45. Waterlogging stress reshapes epigenetic regulation of gene expression in Brassica napus.
  46. Sorbic acid prevents tunicamycin-induced endoplasmic reticulum stress and Ire1-Hac1 pathway activation in Saccharomyces cerevisiae.
  47. Mapping genome-wide RNA-RNA and RNA-DNA interactions in nuclear hubs of male and female Drosophila cells.
  48. Heat shock proteins in male infertility: recent advances and clinical implications.
  49. Circular RNA Translation Modulation via Small Ligand-Mediated Protein Stabilization.
  50. Mechanisms and Current Therapeutic Targets of Podocyte Damage in Diabetic Kidney Disease.
  51. Chromatin immunoprecipitation assay for analyzing histone H3-mediated regulation of copper homeostasis.
  52. Genome-wide characterization of heat shock protein genes reveals thermal stress-responsive candidates in Litopenaeus vannamei.
  53. Heat shock proteins in farmed aquatic animals: advancing animal health and welfare management through building resilience.
  54. Allosteric rewiring of mitochondrial stress signaling through Miro1.
  55. Chronic nitric oxide mediates dual-layer gene regulation through mRNA m6A positional remodeling and parallel transcriptional reprogramming.
  56. Pervasive noise in human pre-mRNA splice site selection.
  57. KDM4A-Driven Epigenetic Reprogramming as a Central Nexus Linking Metabolic Adaptation, Immune Remodeling, and Therapy Resistance in Cancer.
  58. Seed pairing between a small regulatory RNA and target mRNA determines cleavage by a RNase E with a minimal C-terminal scaffold.
  59. Combinatorial sequence elements fine-tune mitochondrial protein import to facilitate dual localization.
  60. A new dimension in protein-RNA interface prediction: Integrating protein language models and geometric deep learning.
  1. RNA. 2026 Aug 17. pii: rna.081039.126. [Epub ahead of print]
    Yeast Rai1p and the RAC complex (Ssz1p/Zuo1p) modulate uORF-mediated GCN4 translational control under stress conditions.
    Kristina Jendruchova, Adriana Subrtova, Leos Shivaya Valasek.
      Translation reinitiation (REI) is one of the most important gene-specific regulatory mechanisms by which eukaryotic cells influence expression of main translons, for example during highly conserved integrated stress response (ISR). In S. cerevisiae, expression of the key stress response gene, GCN4, is controlled by an intricate interplay among four short upstream translons (uTranslons, formerly uORFs), resulting in high or low levels of REI at GCN4 depending on the growth conditions. Under nutrient rich conditions, GCN4 expression is repressed, but upon amino acid starvation, it is derepressed, despite of a general translational shut down. Capitalizing on our screening reporter system, we identified three new factors influencing efficiency of REI after translation of GCN4 uTranslons: Rai1p (an RNA quality control and processing factor), and Ssz1p and Zuo1p (members of the Ribosome Associated Complex [RAC]). Importantly, we showed that depletion of these factors deregulated derepression of Gcn4p synthesis under starvation. Furthermore, we found that similar to RAC, Rai1p associates with 40S subunits and actively translating ribosomes. We also explored interactomes of these proteins. Collectively, we present three previously unknown factors that co-regulate stress response to amino acid starvation in the budding yeast by unique mechanisms.
    Keywords:  GCN4; RAI1; SSZ1 and ZUO1 (RAC complex); ribosome recycling; translation reinitiation
    DOI:  https://doi.org/10.1261/rna.081039.126
  2. J Mol Biol. 2026 Aug 19. pii: S0022-2836(26)00368-2. [Epub ahead of print] 169995
    Codon optimality modulates cellular stress and innate immune responses triggered by exogenous RNAs.
    Chotiwat Seephetdee, Nada Bejar, Kathrina D Castillo, Eric Chau, Thy Y Nguyen, Biana Godin, Daniel L Kiss.
      Despite advancements in RNA sequence design, evidence regarding the preferential use of synonymous codons on cellular stress and innate immune responses is lacking. To this end, we developed a new codon optimality formula to re-engineer the coding sequences of three luciferase reporters. We demonstrate that mRNAs enriched in optimal codons elicited dramatic increases in luciferase activities compared to less optimal sequences both in vitro and in vivo. Notably, transfecting low optimality test RNAs suppress the translation of co-transfected control mRNAs in dual reporter assays. Transcriptomic profiling revealed temporally distinct waves of cellular stress, comprising an early ribotoxic stress response followed by a sustained integrated stress response and interferon-driven innate immune program. Cells responded to both dsRNA contaminants, which was mitigated by cellulose purification, and also rare codon-mediated ribosome stalling signal activating GCN2 independently of dsRNA. Translation suppression by low optimality mRNAs was driven by eIF2α phosphorylation, which was suppressed by a GCN2 inhibitor, but not by other eIF2α kinase inhibitors, and both cellulose purification and GCN2 inhibition each produced partial translational rescue. Using nucleoside-modified or circular RNAs also fully or partially abrogated these responses. Finally, only optimal, circular RNAs have enhanced RNA lifespan and duration of protein expression. Our results show that RNA sequence, composition, and structure all govern RNA translatability. Further, RNA sequences with poor codon optimality are immunogenic and induce cellular stress. Together, we show that RNA coding sequence design is a key consideration for both mRNA and circular RNA therapeutics.
    Keywords:  RNA therapeutics; circRNA; codon optimality; innate immune evasion; reporter assays; stress response
    DOI:  https://doi.org/10.1016/j.jmb.2026.169995
  3. bioRxiv. 2026 Jul 30. pii: 2026.07.29.740946. [Epub ahead of print]
    Anticodon nucleotide modifications affect translational tuning by the ribosomal CAR surface.
    Mitsu Raval, Yancheng Zhou, Mia Wichman, Miki Lynch, Daniel Krizanc, Kelly M Thayer, Michael P Weir.
      Nucleotide modifications of the tRNA anticodon can affect protein translation fidelity and speed. Chemical modifications of the anticodon nucleotide 34 are regulated under cellular stress and associated with several translational defects and pathologies. Here, we investigate how these modifications influence A-site codon recognition interactions and their coupling to the CAR site that lies adjacent to nucleotide 34 in the ribosome. The conserved three-residue CAR interface hydrogen bonds in a sequence-dependent manner to the mRNA +1 codon 3'-adjacent to the A-site codon and is implicated in tuning translational speed. The C of CAR is pi-stacked with the nucleotide 34 of the A site tRNA anticodon. The A site and the CAR site influence each other's hydrogen bonding and stacking interactions, and these codon-adjacency effects potentially provide a layer of regulation affecting translational fidelity and kinetics. Through molecular dynamics simulations of a subsystem of a translocating ribosome IRES-model, we observed that nucleotide 34 modifications affect the hydrogen bonding and stacking interactions at the A site and CAR site as well as CAR's influence on the A site interactions. Integrating these results with gene sequence and ribosome profiling analyses, we propose that nucleotide 34 modifications help modulate CAR's sequence-dependent tuning of translation in response to cellular stress.
    Graphical abstract:
    DOI:  https://doi.org/10.64898/2026.07.29.740946
  4. Circ Res. 2026 Aug 21.
    Single-Molecule Imaging Reveals ERK-Dependent Spatial Translation in Cardiomyocytes.
    Itai Erlich, Guy Douvdevany, Rami Haddad, Benjamin L Prosser, Izhak Kehat.
       BACKGROUND: Translational control of gene expression is crucial in cardiomyocytes, particularly in response to hypertrophic stimuli. The ERK (extracellular signal-regulated kinase) pathway plays a key role in inducing cardiac hypertrophy and regulating specific protein translation. However, it remains unclear how this specificity is achieved, and the spatiotemporal regulation of protein translation is not fully understood.
    METHODS: We used SINAP (single-molecule imaging of nascent peptide) reporters to visualize and analyze the translation dynamics in single adult rat ventricular cardiomyocytes and tracked active translation sites at high spatiotemporal resolution. We also examined the effects of adrenergic stimulation and the role of the ERK pathway in translation localization.
    RESULTS: Our findings revealed that translation sites are primarily localized near Z-lines in cardiomyocytes, with some sites being highly dynamic and moving during translation. The 3' untranslated regions did not significantly change the localization of translation. Many translation sites colocalized with microtubules, and their movement predominantly occurred along microtubular tracks. Adrenergic stimulation led to a transient shift in translation activity toward the perinuclear region, peaking at 12 hours and requiring ERK pathway activity for this localization change. This shift is part of the hypertrophic response and is required for early translation of genes such as Nppa.
    CONCLUSIONS: Our high-resolution single-cell study demonstrates that protein translation in cardiomyocytes is dynamic and responsive to hypertrophic stimuli in an ERK-dependent manner. The localized translation mechanism allows cardiomyocytes to rapidly adapt to changing environments by preferentially translating mRNAs in the perinuclear region. These findings provide new insights into the spatial regulation of translation in cardiomyocytes and its role in cardiac hypertrophy.
    Keywords:  adult; myocytes, cardiac; neurons; phosphorylation; serotonin
    DOI:  https://doi.org/10.1161/CIRCRESAHA.126.329033
  5. bioRxiv. 2026 Jul 28. pii: 2026.07.27.741020. [Epub ahead of print]
    Astrocytes instructively regulate neuronal translation.
    Wendy J Liu, Carson C Schultz, Eshaan A Khan, Mauricio M Oliveira, Srinidhi V Kalavai, Charles J Sheehan, Xunzhao Zhang, Richard Sam, Eric Klann.
      Neuronal protein synthesis is essential for synaptic plasticity and long-term memory, yet whether its regulation is shaped by other cell types remains poorly understood. Here, we show that astrocyte-secreted proteins regulate global neuronal translation depending on astrocytic state. Astrocyte-conditioned medium (ACM) increased neuronal translation under basal conditions, an effect enhanced by astrocyte stimulation with the activity-dependent factor BDNF, whereas ACM from neurotoxic reactive astrocytes, a state linked to neuroinflammation and Alzheimer's disease, suppressed neuronal translation. Across these conditions, neuronal mTORC1 activity consistently tracked with translational output, whereas the integrated stress response (ISR) acted through distinct, state-specific mechanisms that did not always track with neuronal translation. Furthermore, we identified astrocyte-secreted apolipoprotein E (APOE) and its associated cargo as a negative regulator of neuronal translation that contributed to the decreased translation induced by neurotoxic reactive astrocytes. We also found that astrocyte-secreted signals required neuronal endocytosis to influence translation and drove synaptic remodeling dependent on glutamatergic signaling and neuronal mTORC1 activity. Together, these findings identify astrocytes as active, instructive regulators of neuronal translation and synaptic structure, with implications for understanding how astrocyte dysfunction may disrupt the translational mechanisms underlying impairments in synaptic plasticity and long-term memory in neurodegenerative disease.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.64898/2026.07.27.741020
  6. Biochem J. 2026 Aug 20. pii: BCJ20250300. [Epub ahead of print]
    Loss of O-GlcNAc Transferase activity impairs the dynamic formation of protective stress granules in ischemic cardiomyocytes.
    Hannah C Swimm, Wenxi Zhang, Yashas Mallikarjun, Rohit Satish, Andres J Medina, Sabrina Lo, Hisham Qureshi, Aidan J Dunphy, Deepthi Ashok, Agnes Sidor, Olurotimi O Mesubi, Brian O'Rourke, Brian Foster, Natasha Zachara, Kyriakos N Papanicolaou.
      Stress granules are transient biomolecular condensates of proteins and RNA formed during stress. Stress granules support cell survival by sequestering components of the translational machinery, suppressing pro-apoptotic signaling, and conserving cellular resources. O-GlcNAcylation, a dynamic modification of cytoplasmic proteins, is an important regulator of stress responses, including stress-granule assembly. O-GlcNAcylation is protective in acute myocardial stress; however, whether O-GlcNAcylation regulates stress granules to protect cardiomyocytes remains unclear. Here, we investigated whether O-GlcNAcylation regulates stress granule formation in cardiomyocytes exposed to sodium arsenite stress or ischemia/reperfusion injury. G3BP1 is an RNA-binding protein that is essential in stress granule formation. Using a G3BP1-EGFP reporter, we found that OGT, the enzyme responsible for installing O-GlcNAc on target proteins, is necessary for efficient stress-granule formation in cardiomyocytes. Importantly, we identified T268 of G3BP1 as an O-GlcNAcylation site in these cells and demonstrated by mutagenesis its functional importance for stress granule assembly. In primary cardiomyocytes subjected to simulated ischemia/reperfusion, stress granules formed transiently during ischemia, and this response was decreased by OGT-knockdown. Similarly, stress granules were transiently detected at the ischemic phase of ischemia/reperfusion injury, and their numbers were reduced in OGT-deficient hearts. Furthermore, pretreatment with sodium arsenite before ischemia/reperfusion was cardioprotective. Likewise, pretreatment with sodium arsenite protected cells from staurosporine-induced death and this effect was decreased by OGT knockdown. Together, these findings identify OGT and O-GlcNAcylation as important regulators of stress-granule assembly in cardiomyocytes, define G3BP1 as an O-GlcNAc-modified effector, and demonstrate that stress granules can act as cytoprotective mediators during acute cardiac injury.
    Keywords:  G3BP1; Ischemia; O-GlcNAc; Stress Granules; cardiomyocytes; cytoprotection
    DOI:  https://doi.org/10.1042/BCJ20250300
  7. J Biosci. 2026 ;51(33):
    Poly(A)-binding proteins in trypanosomatids and Plasmodium.
    Supratik Das.
      Poly(A)-binding proteins (PABPs) are scaffold proteins that bind to the poly(A) tail of mRNAs and ensure translation fidelity by forming a closed-loop circular mRNA via association with the cap-binding complex. They can be either cytoplasmic or nuclear and play important roles in regulating polyadenylation, deadenylation, translation initiation and termination, mRNA stability, synthesis of the poly(A) tail, regulation of poly(A) length and stimulation of mRNA maturation as well as nuclear export of certain mRNAs. In higher eukaryotes, PABPs are well characterized. However, in pathogenic parasites such as trypanosomatids, belonging to the genera Leishmania and Trypanosoma, as well as Plasmodium, they are not well characterized. Using bioinformatics and computational tools, we have previously studied parasite translation initiation factors such as eIF4E, eIF4G, eIF4A, eIF4B, and Mnk1 kinase and have shown that they vary considerably and differ significantly from human translation initiation factors. In this report, the orthologues of the translation factor PABP in trypanosomatids and Plasmodium are studied. Both conservation and significant differences were observed in PABPs from these pathogenic parasites compared to human PABPs, which should prompt further structure-function studies of these proteins.
    DOI:  https://doi.org/10.1007/s12038-026-00604-z
  8. Genetics. 2026 Aug 19. pii: iyag201. [Epub ahead of print]
    The assembly factors Rei1 and Reh1 share a redundant function in loading ribosomal protein eL24.
    Ran Lin, Madison J Reynolds, Nila R Shankar, Arlen W Johnson.
      The correct assembly of ribosomes is essential for viability and faithful gene expression. In eukaryotic cells, the pre-40S and pre-60S ribosomal subunits are largely pre-assembled in the nucleolus before they are exported to the cytoplasm for final maturation. Although most ribosomal proteins of the large subunit are loaded onto pre-60S particles in the early nucleolar steps, a few, including eL24, are loaded in the cytoplasm. eL24 is thought to recruit the zinc-finger protein Rei1 (ZNF622 in humans). In yeast, Rei1 has a paralog, Reh1. While we and others have previously shown that Rei1 facilitates the removal of Arx1, Rei1 and Reh1 appear to have an additional unknown function. To identify this function, we first examined the protein composition of pre-60S subunits isolated from rei1Δ reh1Δ mutant cells and found that these subunits were specifically defective for eL24. However, the absence of eL24 did not impair Rei1 binding to pre-60S. Moreover, overexpression of eL24 suppressed the growth defect of the double mutant. As an alternative approach to understanding the function of Rei1 and Reh1, we screened for bypass suppressors of the growth defect of rei1Δ reh1Δ cells. We identified mutations in the genes coding for ribosomal protein uL3, the GTPase Lsg1 and the protein phosphatase Ppq1. Importantly, these suppressors all partially reversed the eL24 loading defect of rei1Δ reh1Δ cells. Based on these results, we propose a revised order of cytoplasmic assembly events where Rei1 and Reh1 facilitate the recruitment of eL24 to the pre-60S particle.
    Keywords:  60S ribosomal subunit; Reh1; Rei1; Ribosome assembly; eL24
    DOI:  https://doi.org/10.1093/genetics/iyag201
  9. Front Immunol. 2026 ;17 1912261
    Targeting CPSF73, the mRNA 3' end processing endonuclease, moves cancer cells away from the mesenchymal state.
    Marzieh Naseri, Huiyun Liu, Luyang Wang, Salwa Mohd Mostafa, Ehsan Ranaei Pirmardan, Bin Tian, Claire L Moore.
       Background: Metastasis significantly contributes to cancer-related mortality and therapeutic failure. Cancer cells acquire metastatic potential by losing epithelial characteristics and gaining mesenchymal properties through the epithelial-mesenchymal transition (EMT). Differential poly(A) site (PAS) usage, known as alternative polyadenylation (APA), generates mRNA isoforms differing in coding sequence, subcellular localization, stability, or translation efficiency. In cancer, 3'UTR shortening increases expression of proto-oncogenes by escaping miRNA-mediated repression. High expression of CPSF73, which cleaves mRNA precursors at PASs, is associated with unfavorable prognoses in cancer patients. However, the role of APA in regulating EMT remains poorly understood.
    Methods: In this study, to investigate the role of APA in EMT, we employed JTE-607, a small-molecule inhibitor of CPSF73 activity, to examine the impact of catalytic inhibition of CPSF73 on proliferation and EMT in MDA-MB-231, MCF7, A549, and HepG2 cancer cells. To identify differential usage of PASs, global profiling of APA changes, and differential gene expression analysis were performed in MDA-MB-231 cells. Additionally, antisense oligonucleotides were used to block the use of a specific PAS whose APA change may be a driver of EMT reversal.
    Results: Our findings showed that inhibiting the enzymatic activity of CPSF73 both slows cancer cell growth and moves the cells away from the mesenchymal state across all four cell lines tested. Global profiling of APA changes following CPSF73 inhibition revealed widespread 3'UTR lengthening and suppression of intronic PASs in MDA-MB-231 cells. APA shifts were observed in key EMT-related genes, accompanied by decreased expression of corresponding proteins across all four cell lines. We used antisense morpholino oligonucleotides to block the proximal PAS of AKT2, shifting the balance of AKT2 mRNA isoforms toward the long isoform. This shift caused EMT reversal, marked by reduced AKT2 protein expression, changes in EMT-related markers, and impaired invasion by MDA-MB-231 cells.
    Conclusion: Together, these findings identify APA-mediated 3'UTR lengthening, with functional consequences in EMT-related genes, as a coordinated mechanism leading to an attenuated EMT phenotype, highlighting a significant connection between APA and the EMT process. Interfering with these APA changes may offer a promising therapeutic strategy to suppress metastasis, with potential efficacy across multiple pathways.
    Keywords:  3′ UTR lengthening; Alternative polyadenylation (APA); CPSF73; Epithelial-mesenchymal transition (EMT); JTE-607
    DOI:  https://doi.org/10.3389/fimmu.2026.1912261
  10. Biol Chem. 2026 Aug 18.
    Unmasking the modified small non-coding RNome: detection strategies for RNA modifications.
    Bennett Henzeler, Kathrin Halter, Özge Simsir, Pascal Giehr, Sabine Schneider.
      RNA molecules carry a wide range of chemical modifications that play key roles in regulating their structure, stability, and function. These modifications are especially abundant in small and non-coding RNAs, such as transfer RNAs (tRNA), ribosomal RNA (rRNA), and related fragments, where they influence processes from translation to gene silencing. However, studying these modifications remains challenging due to the short length of these RNAs, their strong secondary structures, and the high density of chemical marks, all of which can interfere with standard sequencing workflows. This review summarizes current strategies for detecting and mapping RNA modifications in the small RNome. We outline the diversity of RNA classes and their characteristic modification patterns, and then discuss key methodological advances. These include demodification-based sequencing approaches for heavily modified RNAs, targeted chemical and enzymatic methods for site-specific mapping, and emerging direct RNA sequencing technologies that allow analysis of native molecules without prior conversion. We also highlight orthogonal validation techniques used to confirm modification identity and improve reliability. Together, these approaches provide complementary insights, but no single method is sufficient on its own. Careful experimental design and validation therefore remain essential for accurate and comprehensive analysis of RNA modifications.
    Keywords:  RNA modifications; chemical modifications; direct RNA sequencing; non-coding RNA; small RNome
    DOI:  https://doi.org/10.1515/hsz-2026-0148
  11. J Theor Biol. 2026 Aug 19. pii: S0022-5193(26)00201-8. [Epub ahead of print] 112576
    A Revised Ribosome-Antibiotic Model with Proportional Feedback Synthesis Explains Recovery from Translation Inhibition.
    Brittany Howell, Matthew Scott.
      Antibiotic resistance remains an urgent challenge in medicine, shaped not only by genetic mechanisms but also by adaptation of bacteria under drug exposure. Comprehending these constraints requires integrating how translational capacity, nutrient supply, and global feedback determine recovery and survival. In this work, we integrate a refined mechanistic model of reversible protein synthesis inhibition with experimental measurements of bacterial growth. Our framework incorporates a metabolically limited recovery phase and a proportional feedback controller that links amino acid supply to ribosome synthesis. These refinements resolve unrealistic recovery dynamics predicted by earlier formulations and capture the physiological adaptation of Escherichia coli observed under pulse-dose exposure to tetracycline in both glucose- and glycerol-based media. The resulting framework unifies steady-state and transient antibiotic responses, explaining how metabolic limitation and feedback regulation shape cellular recovery following translational stress. Clinically, the model supports high-intensity antibiotic pulses of limited duration (on the order of several hours) that maximize inhibition while minimizing the selective window for resistance, providing a quantitative rationale for pulse- and intermittent-dosing strategies.
    Keywords:  bacterial growth physiology; mechanistic modeling; post-antibiotic recovery; ppGpp regulation; proteome allocation; pulse dosing; ribosome-targeting antibiotics
    DOI:  https://doi.org/10.1016/j.jtbi.2026.112576
  12. bioRxiv. 2026 Jul 30. pii: 2026.07.30.740154. [Epub ahead of print]
    Chaperone condensates buffer the heat shock response against pleiotropic inputs.
    Lucas Dyer, Jennifer T Krystosek, Sean A Martin, Cameron Williams, Leah Chaney Winner, Asif Ali, Surabhi Chowdhary, David Pincus.
      Stress response pathways can be specific, dedicated to one stimulus, or pleiotropic, funneling distinct perturbations into a shared program. The heat shock response (HSR), the Hsf1-driven transcriptional program, has been linked to numerous stresses, suggesting it is pleiotropic. Here we find that high amplitude HSR activation is specific to heat shock in budding yeast. Heat shock activates the HSR through a condensate cascade in which orphan ribosomal proteins condense with Sis1 and Hsp70, titrating these chaperones away from their repressive interactions with Hsf1, triggering Hsf1 condensation with the transcriptional machinery, and activating HSR genes. Other stressors likewise drive Sis1 and Hsp70 condensation, redeploying Sis1 to stimulus-specific subcellular sites. However, chaperone condensation is not sufficient to activate the HSR. Sis1 and Hsp70 condense under conditions in which the HSR remains inactive, and Sis1 depletion increases HSR activation under all conditions except heat shock. These results suggest that chaperone condensates buffer the HSR, setting a threshold for activation and imparting specificity.
    DOI:  https://doi.org/10.64898/2026.07.30.740154
  13. Nat Rev Microbiol. 2026 Aug 19.
    Bacterial small regulatory RNAs.
    Kai Papenfort.
      Regulatory RNA molecules have crucial roles in modulating gene expression across diverse biological systems, thereby regulating multiple complex cellular programmes ranging from embryonic development to pathogenesis. In bacteria, regulatory RNAs are expressed in response to various environmental cues and stress conditions, and they are key regulators of virulence and biofilm formation, among others. Most known bacterial RNA regulators belong to the heterogeneous group of small RNAs (sRNAs), which often function together with RNA-binding proteins to base-pair with and modulate target mRNA translation and/or stability. Other bacterial sRNAs regulate protein activity, affect transcription elongation and termination, or detect foreign nucleic acids. Given that a single sRNA often regulates dozens of genes, these regulators have been recognized as rivalling transcription factors in their regulatory actions and contributions to network logic. In this Review, I summarize the regulatory functions of bacterial sRNAs, describe the molecular mechanisms that govern their expression and regulatory consequences, and discuss the many exciting open questions surrounding sRNA-mediated gene regulation in bacteria.
    DOI:  https://doi.org/10.1038/s41579-026-01353-4
  14. J Biol Chem. 2026 Aug 19. pii: S0021-9258(26)02336-7. [Epub ahead of print] 113464
    mRNA translational dynamics mediates totipotent-like reprogramming.
    Lingci Huang, Jun Zhang, Xinwei Wu, Haotian Zhang, Wanting Cai, Xiaoyan Sun, Yuanhui Mao, Jun Zhou, Xiao-Min Liu.
      Embryonic stem cells (ESCs) are characterized by their dual capacity for self-renewal and differentiation into all cell types of the embryonic lineage. A subpopulation known as 2-cell-like cells (2CLCs), which recapitulate key molecular and metabolic features of totipotent 2-cell blastomeres, has been identified within cultured mouse ESC populations. While transcriptional regulation, epigenetic modifications, and chromatin reorganization are known to be critical for the reprogramming of pluripotent ESCs into a totipotent-like state, the role of translational control in this process remains poorly understood. Using an inducible 2CLC model, we performed transcriptome-wide profiling of mRNA translation and found that global translation efficiency dynamically decreases during the early phase of totipotent-like reprogramming, correlating with reduced TORC1 signaling and translation initiation. In the later phase, although overall mitochondrial mass declines, mitochondrial translation is selectively upregulated and exhibits high translational efficiency. Importantly, pharmacological inhibition of mitochondrial translation suppressed the expression of canonical 2-cell transcripts and impaired the transition from ESCs to 2CLCs. Together, these results demonstrate that coordinated regulation of both cytosolic and mitochondrial translation during totipotent-like reprogramming, offering a new perspective for understanding cell fate determination.
    Keywords:  2CLCs; mRNA translation; mitochondrial translation; totipotent
    DOI:  https://doi.org/10.1016/j.jbc.2026.113464
  15. Biochim Biophys Acta Rev Cancer. 2026 Aug 16. pii: S0304-419X(26)00155-1. [Epub ahead of print]1881(5): 189683
    The hypusine circuit: eIF5A at the crossroads of polyamine metabolism, malignant progression, and therapeutic vulnerability.
    Zhihao Wen, Zhaoyang Zeng, Wei Xiong, Chunmei Fan.
      Hypusination of eukaryotic translation initiation factor 5 A (eIF5A) is a highly conserved post-translational modification. This process uniquely depends on spermidine and is catalyzed sequentially by deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Recent studies have established eIF5A hypusination as a key translational regulatory mechanism linking polyamine metabolism to tumor progression. By relieving ribosomal stalling in selected difficult-to-translate targets, hypusinated eIF5A directly controls defined translational outputs. Through these direct mechanisms, as well as broader downstream signaling and phenotypic effects whose immediate translational targets remain incompletely resolved, the hypusination pathway has been linked to tumor cell proliferation, invasion and metastasis, angiogenesis, therapeutic resistance, and adaptive stress responses. This review critically distinguishes sequence-resolved translational mechanisms from target-level regulatory associations and indirect phenotypic consequences through which eIF5A hypusination is linked to these cancer hallmarks and further examines pharmacological and genetic strategies targeting the polyamine-eIF5A axis, including inhibitors of polyamine metabolism, DHPS, and DOHH. It also discusses the potential translational significance of these strategies in cancer therapy. Overall, eIF5A hypusination may act as a central effector that converts metabolic inputs into oncogenic protein outputs and represents a promising therapeutic target across diverse tumor types.
    Keywords:  Hypusination; Polyamine metabolism; Therapeutic vulnerability; Translational control; eIF5A
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189683
  16. iScience. 2026 Aug 21. 29(8): 116529
    Transcriptome-wide splicing analysis reveals HuR-regulated post-transcriptional programs in osteocytes.
    Ziqiu Fan, Aseel Marahleh, Hideki Kitaura, Jiayi Ren, Abdulrahman Mousa, Fumitoshi Ohori, Kuniyasu Niizuma, Sherif Rashad, Hiroyasu Kanetaka.
      Post-transcriptional gene regulation is central to maintaining cellular homeostasis. Among its mechanisms, alternative splicing (AS) fine-tunes cellular adaptation to stress. This study employed an approach combining RNA splicing analysis with RNA-binding protein (RBP) motif enrichment in primary osteocytes cultured in high-glucose conditions. Our analysis identified the RBP human antigen R (HuR) as a top candidate associated with AS regulation. Loss of HuR reshaped the transcriptome through gene expression and splicing changes, converging on two major pathways: stress response and translational control. Functional validation revealed that HuR depletion heightened oxidative stress, impaired mitochondrial function, and rewired key translational signals, while preserving global protein output. Mechanistically, we identified TXNIP mRNA-protein uncoupling following HuR knockdown (KD), characterized by elevated mRNA but reduced protein expression. Collectively, these findings support HuR's role as a key post-transcriptional regulator of osteocyte metabolic adaptation under high-glucose stress, with potential implications for hyperglycemic bone fragility.
    Keywords:  HuR/Elavl1; RNA-binding proteins; TXNIP; alternative splicing; hyperglycemia; mTOR; osteocytes; translation
    DOI:  https://doi.org/10.1016/j.isci.2026.116529
  17. MicroPubl Biol. 2026 ;2026
    The methyltransferase Rrp8 is a positive regulator of autophagy flux in Saccharomyces cerevisiae.
    Swaroopa Badenahalli Narasimhaiah, Elizabeth Delorme-Axford.
      Macroautophagy (hereafter referred to as autophagy) is a dynamic pathway of cellular degradation and recycling that is conserved from yeast to humans. The products of autophagic degradation may be used for anabolic reactions during nutrient-limited conditions. Thus, autophagy serves both metabolic and quality control functions. However, the role of nucleolar proteins in autophagy remains largely unexplored. Here we identify Ribosomal RNA processing 8 (Rrp8) as a positive regulator of autophagy flux in the yeast Saccharomyces cerevisiae. Our work provides insight into the role of the conserved nucleolar protein Rrp8 in regulating cellular responses to starvation.
    DOI:  https://doi.org/10.17912/micropub.biology.002252
  18. J Cell Sci. 2026 Aug 21. pii: jcs.264801. [Epub ahead of print]
    Chronic stress disrupts the network among stress granules, P-bodies, and motor proteins.
    Yuichiro Adachi, Masashi Masuda, Yutaka Taketani, Paul J Anderson, Pavel V Ivanov.
      Stress granules (SGs) are dynamic RNA condensates that assemble rapidly in response to cellular stress following translational arrest, thereby promoting adaptation and influencing disease pathogenesis. Although SG assembly and disassembly during acute stress have been extensively characterized, their regulation under chronic stress remains poorly understood. We previously showed that chronic stress preconditioning suppresses the earliest stages of SG assembly through translation-dependent mechanisms. Whether chronic stress also impairs subsequent SG maturation has remained unknown. Here, we demonstrate that chronic stress limits SG maturation by disrupting the MYH9-dependent interaction network centered on the core SG nucleator G3BP1. Loss of this interaction reduces SG size and impairs docking between SGs and processing bodies (PBs), thereby restricting the maturation of nascent SGs. In parallel, chronic stress decreases expression of the SG nucleator UBAP2L, an essential regulator of SG-PB docking, further exacerbating these defects. Together, our findings identify chronic stress as a regulator of the MYH9-G3BP1-UBAP2L axis and reveal that chronic stress inhibits SG maturation through translation-independent mechanisms.
    Keywords:  G3BPs; MYH9; P-bodies; Stress granules; UBAP2L
    DOI:  https://doi.org/10.1242/jcs.264801
  19. bioRxiv. 2026 Aug 07. pii: 2026.08.06.742952. [Epub ahead of print]
    BAG6-RNF115 Couples Protein Quality Control with Ribosome Assembly.
    Anat Raiff, Colin Zenge, Alban Ordureau, Itay Koren.
      Protein homeostasis relies on protein quality control (PQC) pathways that survey the proteome to eliminate aberrant polypeptides. The BAG6 complex is a central PQC factor that recognizes exposed hydrophobic regions, a feature commonly associated with misfolded, mislocalized, and mistranslated proteins. Whether this surveillance machinery also regulates intact, functional proteins as part of physiological proteostasis has remained unclear. Using unbiased quantitative proteomics, we identify the ribosomal protein RPL22L1 as an endogenous BAG6 substrate whose abundance is controlled by continuous proteasomal degradation. This turnover requires the RNF115 E3 ligase activity but not the canonical BAG6 partner RNF126, defining RPL22L1 as a selective RNF115-dependent substrate. Mechanistically, we map a bipartite hydrophobic degron that distinguishes RPL22L1 from its stable paralog RPL22, and show that BAG6-RNF115-mediated degradation is governed by substrate assembly state. Accordingly, RPL22L1 is protected from degradation upon incorporation into the 60S ribosome, where it substitutes for RPL22. When RPL22 is lost, either genetically or through recurrent inactivating mutations in microsatellite-unstable cancers, the vacant ribosomal binding site permits RPL22L1 incorporation, protecting it from BAG6-mediated degradation. These findings establish unassembly-coupled degradation as a mechanism by which BAG6 regulates the abundance of functional protein components, ensuring that they accumulate only when incorporated into their native macromolecular complexes.
    DOI:  https://doi.org/10.64898/2026.08.06.742952
  20. Nucleic Acids Res. 2026 Aug 10. pii: gkag797. [Epub ahead of print]54(15):
    RPL41 stabilizes ribosome dynamics and supports long-protein homeostasis in mammals.
    Mina Hirata, Maho Fujino, Kazuya Ichihara, Ronghao Tang, Momoko Narita, Wakana Iwasaki, Chisa Shiraishi, Taichi Shiraishi, Atsushi Hatano, Toru Suzuki, Tokichiro Abe, Tomoyo Takami, Emi Mishiro-Sato, Atsushi Toyoda, Masaki Matsumoto, Yoshikazu Tanaka, Takuhiro Ito, Toshifumi Inada, Keiichi I Nakayama, Takeshi Yokoyama, Akinobu Matsumoto.
      Ribosomal protein L41 (RPL41 or eL41) is the smallest ribosomal protein and forms the eukaryote-specific bridge, eB14, near the decoding center; however, its role in mammalian translation remains unclear. In this study, we established RPL41-deficient models of human HEK293T cells and mice to define its function. Cryo-electron microscopy revealed that RPL41 constrains intersubunit conformational dynamics without inducing major local static rearrangements. Loss of RPL41 altered A-site dynamics, slowed elongation, modestly increased amino acid misincorporation, and modestly enhanced readthrough of collision-inducing reporter sequences. Quantitative proteomic analysis suggested that these translational defects compromise long-protein homeostasis, as evidenced by increased insolubility and reduced abundance of long proteins. In vivo, Rpl41-/- mice were viable but exhibited growth retardation and decreased abundance of long proteins in tissues. Our findings reveal a conserved role for RPL41 in maintaining ribosome dynamics and translational fidelity, indicating that RPL41 supports ribosome function and long-protein homeostasis in mammals.
    DOI:  https://doi.org/10.1093/nar/gkag797
  21. bioRxiv. 2026 Jul 31. pii: 2026.07.31.741769. [Epub ahead of print]
    Competing Molecular Interactions Govern the Dynamical Arrest of G3BP1 Condensates.
    Anurag Singh, Vicky Liu, Tharun Selvam Mahendran, Aoon Rizvi, Bhargavi Gindra, Brian Freibaum, Hong Joo Kim, J Paul Taylor, Rohit V Pappu, Priya R Banerjee.
      G3BP1 is a central scaffold of stress granules (SGs). Upon cellular stress, G3BP1 forms complex coacervates with translationally repressed mRNAs and recruits multiple RNA-binding proteins to form reversible biomolecular condensates. Persistent SGs are linked to age-dependent dynamical arrest and impaired disassembly. Here, we employ active and passive nanoscale rheology with optical tweezers to show that G3BP1 condensates evolve from being dominantly viscous fluids to dynamically arrested network glasses characterized by nanoscale caging and elastic memory. Integrating atomistic and coarse-grained simulations with experiments, we find that electrostatic interactions between the oppositely charged intrinsically disordered regions drive condensate ageing. RNA modulates these interactions in a length-and structure-dependent manner, delaying dynamic arrest, whereas Caprin-1 binding to the NTF2L domain has little effect. Together, these findings reveal how competing inter-IDR and IDR-RNA interactions govern condensate ageing and material-state transitions. The findings have broader implications for the regulation of SG dynamics in cells.
    DOI:  https://doi.org/10.64898/2026.07.31.741769
  22. Redox Biol. 2026 Aug 07. pii: S2213-2317(26)00335-6. [Epub ahead of print]96 104336
    Selenoprotein S associates with complexes governing membrane protein biogenesis and translation-associated processes.
    Farid Ghelichkhani, Mariia A Kapitonova, Atinuke Odunsi, Erfan Rahmani, Omar G Rosas Bringas, Mohammed Hanzala Kaniyar, John LaCava, Sharon Rozovsky.
      Human selenoprotein S (selenos) is part of the integrated cellular stress response and linked to protein quality control and signaling pathways. Consequently, genetic polymorphisms of selenos are associated with increased risks for diabetes, dyslipidemia, and cardiovascular diseases. Determining the specific roles of selenos in these cellular pathways and diseases has been challenging, as selenos associates with a wide range of protein complexes. Thus, to map the cellular functions of selenos and uncover their interconnections, we used affinity purification and in vivo crosslinking to stabilize transient protein interactions, followed by proteomics to record the resulting selenos interactome. Through mapping of selenos protein partners, we found evidence that selenos associates with complexes responsible for the insertion of membrane proteins into the endoplasmic reticulum (ER) bilayer and their connected quality control components. Furthermore, selenos is also part of metabolic, trafficking, and mitochondrial pathways. Notably, proteins involved in translation preferentially associate with selenos when its C-terminal intrinsically disordered segment containing the redox-active motif is accessible. Together, these results identify the C-terminal redox loop of selenos as a central interaction hub connecting translation with ER membrane protein biogenesis and quality control.
    Keywords:  Derlin; EMC; Selenoprotein S; Selenos; VCP; VIMP
    DOI:  https://doi.org/10.1016/j.redox.2026.104336
  23. Plant Genome. 2026 Sep;19(3): e70291
    Focus on DnaJ protein research from Arabidopsis to crop improvement.
    Muhammad Arif, Hafiz Mamoon Rehman, Sehrish Bashir, Noman Mahmood, Atul Kumar Srivastava, Yakov Kuzyakov, Moh Sajid Ansari, Hon-Ming Lam, Mingfang Yang.
      DnaJ proteins (Hsp40s) are essential components of the cellular proteostasis network, functioning as molecular co-chaperones that regulate protein folding, stability, and stress-responsive homeostasis in plants. Beyond their classical role as Hsp70 partners, accumulating evidence demonstrates that DnaJ proteins participate in diverse biological processes by integrating proteostasis with hormonal, developmental, and defense signaling pathways. This review synthesizes recent advances in the structural diversity, evolutionary distribution, and functional specialization of DnaJ proteins across model plants and crops, including Arabidopsis, rice, maize, tomato, soybean, grapevine, citrus, cucumber, and other economically important species. We summarize mechanistic evidence demonstrating their involvement in abiotic stress tolerance, including heat, drought, salinity, osmotic, oxidative, and cold stress, through regulation of protein quality control, reactive oxygen species detoxification, ion homeostasis, abscisic acid and melatonin signaling, and transcriptional stress networks. Emerging studies further reveal their roles in biotic stress responses by modulating immune signaling, pathogen resistance, and host-microbe interactions, while additional evidence links DnaJ proteins to reproductive development, root architecture, chloroplast stability, fruit ripening, and postharvest quality maintenance. Advances in genome-wide identification, transcriptomic profiling, gene editing, transgenic validation, and functional genomics have substantially expanded understanding of DnaJ-mediated molecular networks and their contributions to climate resilience. By integrating mechanistic biology with translational breeding strategies, this review highlights DnaJ proteins as promising molecular targets for crop improvement and climate-smart agriculture aimed at increasing productivity, stress tolerance, and postharvest performance under changing environmental conditions.
    DOI:  https://doi.org/10.1002/tpg2.70291
  24. Andrology. 2026 Aug 20.
    YTHDF3-Dependent m6A Modification of cGAS Drives Nanoparticle-Induced Senescence in Spermatocytes.
    Jiayi Liang, Wei Zhang, Huiwen Kang, Ziyan Wang, Ziyan Liu, Danyang Huang, Guangyu Jiang, Lianrui Duan, Ai Gao.
       BACKGROUND: Nanoplastics (NPs), owing to their small size and ability to cross the blood-testis barrier, pose a potential risk to the male reproductive system. However, the molecular mechanisms underlying NP-induced reproductive toxicity, particularly cell senescence, remain poorly understood.
    OBJECTIVES: This study aims to investigate the mechanisms by which polystyrene nanoplastics (PS-NPs) induce spermatocyte senescence, with a particular focus on the role of YTHDF3-mediated m6A RNA methylation in regulating the cGAS-NF-κB signaling pathway.
    MATERIALS AND METHODS: Exposure was established in male C57BL/6 mice via tracheal instillation of PS-NPs, supplemented with spermatogonial cells (GC-2). Testicular dysfunction and spermatocyte senescence were assessed. Further investigations focused on m6A modification and the cGAS-NF-κB signaling axis. Functional studies and knockout experiments were conducted to investigate the role of YTHDF3 and its phase separation.
    RESULTS: PS-NPs exposure led to disrupted testicular architecture, decreased sperm quality, and induced spermatocyte senescence in a concentration-dependent manner. Mechanistically, PS-NPs activated the cGAS-NF-κB signaling axis, resulting in reduced mitochondrial membrane potential and impaired mitochondrial function. This activation not only promoted senescence but also suppressed antioxidant defenses, accelerating the aging process. Epigenetically, PS-NPs upregulated the m6A methyltransferase METTL3 and the reader protein YTHDF3. YTHDF3 underwent liquid-liquid phase separation (LLPS) to form intracellular condensates, directly binding to m6A-modified sites on cGAS mRNA and regulating its stability. Knockdown of YTHDF3 significantly attenuated cGAS activation and alleviated the senescence phenotype.
    DISCUSSION AND CONCLUSION: This study identifies a novel mechanism where YTHDF3-mediated m6A modification, driven by phase separation, activates the cGAS-NF-κB pathway in response to PS-NPs, leading to mitochondrial damage and spermatocyte senescence. These findings provide new insights into the epigenetic and phase separation-based mechanisms of nanoplastic reproductive toxicity and suggest potential intervention strategies targeting m6A modification, phase separation, or the cGAS pathway.
    Keywords:  NPs; m6A modification; male reproductive damage; spermatocyte senescence
    DOI:  https://doi.org/10.1111/andr.70357
  25. Proc Natl Acad Sci U S A. 2026 Aug 25. 123(34): e2534903123
    Human Hsp70 paralogs display selective J-domain interactions tuning proteostasis under stress.
    Roni Suhler, Lars J W van Beurden, Merav D Shmueli, Ofrah Faust, Rina Rosenzweig.
      Hsp70 chaperones are central regulators of proteostasis, mediating folding, refolding, degradation, and aggregation-prevention. Their activity is tuned by the diverse J-domain proteins (JDPs), which both recruit client proteins and stimulate Hsp70 ATP hydrolysis via interaction with a conserved J-domain. The cytosol contains four Hsp70 paralogs-the stress-inducible HSPA1A/B and HSPA6, and the constitutively expressed HSPA8. Whether these act redundantly or carry distinct cellular functions has remained unresolved. Here, we systematically map the interactions of cytosolic Hsp70s with broad-specificity JDPs to elucidate how paralog identity shapes cellular function. We found that despite the high conservation of the JDP-Hsp70 interaction sites, the affinities of these interactions and their functionality varied greatly. HSPA8 behaves as a generalist, engaging all JDP classes with comparable affinity, consistent with its housekeeping role. By contrast, HSPA1 preferentially binds canonical Class A and B JDPs, while showing only weak binding to Class B'. Therefore, under stress, HSPA1 pairs only with Class A/B JDPs to support robust protein refolding, while freeing Class B' to suppress protein aggregation in an Hsp70-independent manner. Most unexpectedly, HSPA6, the most stress-inducible paralog, binds selectivity to Class B JDPs, losing interactions with both Class A and B'. Thus, under severe stress, HSPA6 works exclusively with Class B JDPs to ensure ATP-dependent protein repair, while freeing Class A and B' JDPs to act independently of Hsp70 to protect damaged/misfolded proteins. Our findings reveal an evolved hierarchy of paralog-specific JDP couplings that dynamically rewires the Hsp70 network from active repair to protection during stress.
    Keywords:  Hsp70 and J-domain proteins; NMR; molecular chaperones; protein folding and aggregation; protein homeostasis
    DOI:  https://doi.org/10.1073/pnas.2534903123
  26. Sci Rep. 2026 08 18. pii: 25916. [Epub ahead of print]16(1):
    The lncRNA PHAROH augments MYC mRNA levels in insulin-producing cells by counteracting TIA1-induced MYC silencing.
    Tongjian Zhao, Nils Welsh.
      Type 1 and type 2 diabetes are characterized by beta cell dysfunction and insulin deficiency, and the appropriate turnover of MYC expression appears to control the beta-cell fate. Therefore, it is important to better understand the mechanism that controls MYC expression. Hence, the current study aimed to elucidate the interactions of the long non-coding RNA molecule PHAROH at the interface of MYC mRNA and the RNA-binding protein TIA1. For this purpose, we studied MYC mRNA levels in glucagon-producing alpha-TC1-6 cells, insulin-producing MIN6 cells, and in human pancreatic islets. We observed that in insulin-producing cells, but not in alpha cells, MYC mRNA levels were increased in response to stress (proinflammatory cytokines or palmitate + high glucose). Levels of PHAROH were also increased in insulin-producing cells, but not in glucagon-producing cells. To evaluate whether the increased PHAROH levels participated in the induction of MYC mRNA, we treated MIN6 cells with synthetic antisense LNA GapmeR oligonucleotides (ASO) designed to target PHAROH. We observed that the PHAROH ASO 1 increased both PHAROH and MYC mRNA expression. MYC protein levels were also increased by PHAROH ASO 1, both in the absence and presence of pro-inflammatory cytokines. Using an RNA immunoprecipitation strategy, we observed that PHAROH ASO 1 decreased MYC mRNA binding to TIA1, and instead increased PHAROH binding to TIA1. It is concluded that beta cells increase their MYC expression during stress and that this occurs via increased PHAROH-mediated sequestration of TIA1 and subsequent release of MYC mRNA from TIA1-induced inhibition.
    Keywords:  Beta cell; MYC; RNA-binding protein; T-cell intracellular antigen 1; lncRNA
    DOI:  https://doi.org/10.1038/s41598-026-65911-9
  27. Trends Biochem Sci. 2026 Aug 21. pii: S0968-0004(26)00246-X. [Epub ahead of print]
    A formyl axis links metabolism to translation.
    Christof Niehrs.
      Initiator methionine tRNA is a key regulator of translation and cell growth. Recent work places formyl chemistry as a regulatory nexus across three molecular layers. In the protein layer, N-formylmethionine supports initiator tRNA recognition and stress-responsive proteostasis pathways. In the RNA layer, 5-formylcytidine at C34 of mitochondrial tRNAMet expands AUG/AUA decoding. In the DNA layer, 5-formylcytosine activates polymerase III transcription of tRNAiMet gene clusters during frog zygotic genome activation. Despite distinct formylation routes and readouts, these layers converge on translational regulation and share metabolic dependencies. One-carbon metabolism supplies methyl/formyl precursors, while mitochondrial and oxidative states influence formyl-mark installation through redox balance and α-ketoglutarate-dependent dioxygenase activity. Together, these layers suggest a formyl-dependent rheostat linking metabolic state to translation capacity.
    Keywords:  2-oxoglutarate-dependent oxygenases; epigenetic reprogramming; epitranscriptomics; folate cycle; mitochondrial gene expression; tRNA modification
    DOI:  https://doi.org/10.1016/j.tibs.2026.08.001
  28. Nucleic Acids Res. 2026 Aug 10. pii: gkag840. [Epub ahead of print]54(15):
    Interplay between stress granule-like structures and nuclear RNA export in a heat shock-specific manner.
    Hosung Jeon, Donghwan Shin, Yeongyo Son, Jiyeun Park, Dong Jae Lee, Jae Sung Shim, Dae-Geun Song, Hokyoung Son.
      When stress strikes, cells initiate adaptive responses, including perturbation of RNA splicing, modulation of nuclear RNA export, and formation of stress granules (SGs). Despite their central role, the composition and regulation of fungal SGs remain poorly understood. Here, we report the formation of heat shock-induced SG-like structures in Fusarium graminearum. Through purification of SG-like structures followed by RNA-sequencing, we performed a transcriptome-wide characterization of their associated transcripts and found that heat shock induces a distinct enrichment of intron-containing transcripts within SG-like structures compared to physiological conditions. Moreover, these SG-like structures co-localize with the nuclear RNA export factor FgYra1 in the nucleus, linking SG-like structures to the RNA export system. Furthermore, transcripts associated with SG-like structures exhibit distinct nuclear retention behaviors during heat shock, and the loss of FgYRA1 alters nuclear retention in an atypical manner. Together, this study defines the molecular architecture of F. graminearum SG-like structures and highlights their functional relevance in coordinating nuclear RNA export during heat shock.
    DOI:  https://doi.org/10.1093/nar/gkag840
  29. Cancer Metastasis Rev. 2026 Aug 15. pii: 58. [Epub ahead of print]45(3):
    N-Acetyltransferase 10 (NAT10) at the crossroads of metabolism, immunology, and cancer biology.
    Peng Xu, Qin Yan.
      The multi-functional protein N-acetyltransferase 10 (NAT10), highly conserved from bacteria to human, is a versatile enzyme with an N-acetyltransferase domain, an RNA helicase domain, and a tRNA-binding domain, known for its ability to acetylate proteins and multiple RNA species. Specifically, NAT10 was reported to catalyze the N4-acetylcytidine (ac4C) modification on tRNA, rRNA, mRNA, and even viral RNA and to regulate translation efficiency, RNA stability, and eventually gene expression. NAT10 draws increasing attention for its emerging roles in rewiring metabolism, including amino acid, lipid, and glucose metabolism, and modulating immune responses to drive cancer progression, metastasis, and therapeutic resistance. In this review, we provide a conceptual framework of how the dysfunction of the highly conserved NAT10 leads to tumorigenesis, metastasis, and therapeutic resistance. We also summarize the major findings that reveal how NAT10 regulates cancer metabolism and immune responses. Lastly, we review the opportunities and challenges of targeting NAT10 to treat cancer and overcome drug resistance.
    Keywords:  Drug resistance; Immunology; Metabolism; Metastasis; N4-acetylcytidine (ac4C); NAT10
    DOI:  https://doi.org/10.1007/s10555-026-10369-4
  30. J Vis Exp. 2026 Aug 14.
    Measuring Live-Cell mRNA Translational Dynamics with Split Luminescent Tagging in HEK293 Cells.
    Christopher A P Batho, Camilla Ascanelli, Megan L Maple, Catherine H Wilson.
      The swift vaccine development to combat COVID-19 illustrated the potential for messenger RNA (mRNA) therapeutics to transform drug development. Like mature mRNA, in vitro transcribed mRNA possesses the same elements including a 5' cap, untranslated regions (UTRs), coding sequence and a poly(A) tail. Previous work studying the effects these components have on mRNA translation has primarily utilized highly engineered reporter proteins which exhibit efficient translation and protein stability. With the structural elements of each mRNA differentially affecting their translation, it is imperative to identify the optimal design relevant to the therapeutic protein of interest (POI). To enable POI translation characterization, a split luciferase complementation system was employed. A short peptide tag (HiBiT), which can be fused to either terminus of the POI, associates with its complementary heterodimer (LgBiT) to reconstitute enzymatic activity in the presence of a cell-permeable substrate. To date, split luminescent tagging has been primarily used for high-throughput protein turnover studies. We have previously demonstrated how split luminescent tagging can be employed to enable high-throughput quantification of mRNA translation temporally in cellulo in HEK293 cells constitutively expressing the complementary heterodimer. Here, we further demonstrate the versatility of the assay and detail how this assay can be employed for optimizing in vitro transcription to reduce costs. The assay system can uniquely distinguish alterations in structural components whilst highlighting the effects of coding sequence optimization using non-engineered genes. Additionally, we demonstrate that a 4-fold reduction in 5' cap concentration for in vitro transcription results in equivalent translation in cellulo. These findings illustrate how split luminescent tagging can be easily integrated into the mRNA therapeutic workflow, enabling monitoring of real-time mRNA-driven protein expression dynamics in cellulo thereby offering a versatile method for the advancement of mRNA-based therapeutics.
    DOI:  https://doi.org/10.3791/70840
  31. IUBMB Life. 2026 Aug;78(8): e70127
    Exercise as a Programmable Regulator of Mitophagy Sensitivity in Aging Muscle and Age-Related Disease.
    Peng Ran, Lifang Yang.
      Aging is increasingly recognized as a systems-level process marked by progressive deterioration of mitochondrial performance in tissues with high energetic demand, placing skeletal muscle at the center of systemic metabolic and functional decline. Beyond its mechanical role, skeletal muscle acts as a regulatory hub for energy homeostasis, redox balance, and inter-organ signaling, functions that depend critically on effective mitochondrial quality control. Emerging evidence indicates that age-related mitochondrial dysfunction arises not only from impaired biogenesis but also from dysregulated mitophagy, the selective autophagic removal of damaged mitochondria. Mitophagy is now understood as a dynamic, context-sensitive process integrating metabolic state, mechanical loading, and cellular stress, rather than a binary response to severe mitochondrial damage. Exercise represents a uniquely potent, non-pharmacological modulator of this process. By transiently perturbing cellular energy balance, calcium flux, and redox signaling, physical activity activates coordinated mitophagic and biogenic programs that promote mitochondrial renewal without precipitating energetic collapse. In contrast to chronic pathological stressors, exercise induces pulsatile, recoverable mitochondrial challenges that recalibrate quality-control thresholds. Importantly, mitophagic responses to exercise are heterogeneous and nonlinear. Exercise modality, intensity, frequency, and temporal organization generate distinct mitochondrial signals, producing fiber-type-specific and age-dependent adaptations. In aging muscle, elevated activation thresholds, delayed clearance kinetics, and lysosomal constraints frequently blunt adaptive mitophagy, indicating remodeling rather than a simple suppression of quality-control logic. This review integrates molecular, physiological, and translational evidence to redefine exercise as a precision regulator of mitophagy in aging skeletal muscle. This review proposes that tailored exercise strategies targeting mitophagy may provide a scalable, non-pharmacological approach to preserve mitochondrial quality and functional resilience during aging.
    Keywords:  aging; exercise; healthspan; mitochondrial quality control; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1002/iub.70127
  32. Genes Dev. 2026 Aug 21.
    Guardians of splicing: quality control mechanisms of snRNA variants.
    Harihar Milaganur Mohan, Roy Parker.
      A new study by Ma and colleagues (doi:10.1101/gad.353690.126) identifies distinct quality control systems that degrade snRNA variants. Variants expressed from snRNA pseudogenes, deficient in 3' end processing or RNP assembly, are degraded by the nuclear RNA exosome or by cytoplasmic decay initiated by TUT4/7 enzymes. When variant snRNAs are stabilized, they can assemble into spliceosomes and alter splicing. Moreover, pathogenic mutations in canonical snRNA genes can trigger aberrant degradation by these quality control mechanisms, which may contribute to disease pathology. In summary, this work reveals how cells maintain a functional pool of snRNP complexes and links their dysregulation to human diseases.
    Keywords:  INTS11; NEXT–exosome; TUT4; TUT7; neurodevelopmental disorders (NDD); pseudogenes; quality control; snRNA; spliceosome; splicing
    DOI:  https://doi.org/10.1101/gad.354115.126
  33. Cell Rep. 2026 Aug 17. pii: S2211-1247(26)00862-4. [Epub ahead of print]45(8): 117784
    Deubiquitylase OTUD3 regulates integrated stress response to suppress progression and sorafenib resistance of liver cancer.
    Hongmiao Dai, Bo Wu, Yingwei Ge, Yang Hao, Lijie Zhou, Ruolin Hong, Jinhao Zhang, Wenli Jiang, Yuting Zhang, Hongchang Li, Lingqiang Zhang.
      
    DOI:  https://doi.org/10.1016/j.celrep.2026.117784
  34. Sci Adv. 2026 Aug 21. 12(34): eaed6318
    Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
    Joan Blanco-Fernandez, Miriam Lisci, Mads M Foged, Chloé Chapuis, Tim Pflästerer, Tatjana Kleele, Alexis A Jourdain.
      Mitochondria drive cellular reprogramming by integrating metabolism and signaling. In macrophages, mitochondria are central to immunometabolic responses to external cues, but the extent to which they are remodeled and participate in macrophage reprogramming remains unclear. Here, we integrate transcriptomics with whole-cell and purified mitochondrial proteomics to profile lipopolysaccharide (LPS)/interferon-γ (IFN-γ)- and interleukin-4 (IL-4)/IL-13-stimulated macrophages. We reveal a notable disconnect between mitochondrial transcript and protein levels following either stimulus and a signal transducer and activator of transcription 6 (STAT6)-dependent increase in mitochondrial DNA (mtDNA) expression and intramitochondrial translation in IL-4/IL-13 macrophages. We demonstrate that pharmacological inhibition of mitochondrial translation or individual respiratory chain complexes variably impairs reprogramming, whereas ATP synthase inhibition uniquely triggers a heme-regulated inhibitor (HRI)-dependent integrated stress response (ISR) through mitochondrial hyperpolarization, thereby preventing IL-4/IL-13 reprogramming. Mechanistically, we show that restoring mitochondrial membrane potential or inhibiting the ISR rescues IL-4/IL-13-mediated reprogramming. Together, we identify mtDNA expression, intramitochondrial translation, and mitochondrial membrane potential as critical, drug-sensitive determinants of the IL-4/IL-13 response.
    DOI:  https://doi.org/10.1126/sciadv.aed6318
  35. Poult Sci. 2026 Aug 04. pii: S0032-5791(26)01206-X. [Epub ahead of print]105(11): 107573
    N6-methyladenosine (m6A) RNA methylation in poultry growth, reproduction, metabolism, and disease: a review.
    Yan Yang, Lin Chen, Zhanhong Zheng, Gaofeng Cai, Jianzhen Huang.
      N6-methyladenosine (m6A) is one of the most abundant internal chemical modifications in eukaryotic RNA. Advances in sequencing technology have driven m6A research in poultry. Partial m6A transcriptome maps have been constructed in species such as chickens, ducks, and geese, and the associations and potential functions of m6A in muscle development, reproductive regulation, nutrient metabolism, stress responses, and infectious diseases have been increasingly characterized. Current poultry m6A studies remain relatively scattered, and a dedicated synthesis of this field is still lacking. To address this gap, this review integrates relevant studies published in poultry over the past decade and summarizes research linking m6A modification to skeletal muscle growth and myofiber-type transitions, intramuscular fat deposition, follicle selection and laying performance, primordial germ cell formation, lipid metabolism and fatty liver development, nutritional regulation, chronic stress, and viral and bacterial infections. The review also examines the current limitations of poultry m6A research and identifies priorities for future research.
    Keywords:  Epitranscriptome; N(6)-methyladenosine; Poultry; RNA modification
    DOI:  https://doi.org/10.1016/j.psj.2026.107573
  36. Angiogenesis. 2026 Aug 20. pii: 61. [Epub ahead of print]29(4):
    Antisense oligonucleotide-mediated disruption of mRNA localisation inhibits angiogenesis.
    Josy Augustine, Precious O Owuamalam, Jennifer Nicell, Peter Barabas, Susanta Chatterjee, Michael O'Hare, Tim M Curtis, Guilherme Costa.
      mRNA localisation is a critical posttranscriptional mechanism that confers a spatiotemporal dimension to the control of gene expression. Among diverse outcomes, this process can result in compartmentalised protein synthesis and consequently, elicit localised cellular responses. Targeting mRNAs to their destination is often determined by localisation elements (LEs) contained in untranslated regions within targeted transcripts. Although mRNA localisation has been widely explored in the context of subcellular biology, its roles in tissue function are only just beginning to emerge. A defined set of transcripts accumulate at the leading edge of endothelial tip cells that guide emerging vessels during sprouting angiogenesis. This includes RAB13 and NET1 mRNAs, which encode proteins implicated in cytoskeletal remodelling processes underpinning cell motility. In this study, we tested the anti-angiogenic potential of antisense oligonucleotide (ASO)-based strategies designed to perturb RAB13 and NET1 localisation. Upon confirming that ASOs targeting LEs mislocalise these mRNAs without altering steady-state levels of the encoded proteins, we applied them to a series of in vitro, ex vivo and in vivo angiogenesis assays. Remarkably, the mislocalisation of RAB13 and NET1 inhibits chemotaxis and vessel sprouting in response to pro-angiogenic stimuli. Furthermore, vessel sprouting from mouse choroidal explants and retinal angiogenesis are also hindered by mRNA mislocalisation. Altogether, our strategy for disrupting spatial control of gene expression in endothelial cells opens new mechanistic avenues for the manipulation of vessel formation.
    Keywords:  Angiogenic sprouting; Antisense oligonucleotides; Endothelial cells; mRNA localisation
    DOI:  https://doi.org/10.1007/s10456-026-10087-z
  37. Mediators Inflamm. 2026 ;2026(1): e4365859
    Haikun Shenxi Capsule Alleviates Renal Fibrosis in CKD Mice by Targeting the METTL3/IGF2BP3-Mediated m6A Modification of NKD2.
    Mingjia Gu, Le Yang, Anjing Xu, Neng Bao, Ying Ni, Fang Cao, Xuejing Gu, Kejian Wen, Xiaolan Cheng.
       BACKGROUND: Renal fibrosis is a central pathological process in chronic kidney disease (CKD). Although Haikun Shenxi Capsule (HKSX) has shown clinical efficacy in CKD, its precise molecular targets and mechanisms remain unclear.
    OBJECTIVE: This study aims to determine whether HKSX exerts antifibrotic effects in CKD by modulating NKD2 expression via METTL3-mediated m6A pathway.
    METHODS: A CKD mouse model was established by unilateral ureteral obstruction (UUO). Mice were divided into Sham, Model, low-dose HKSX, high-dose HKSX, and positive drug groups. Renal pathology and fibrosis were assessed by H&E, Masson's trichrome, and Sirius red staining. Renal function was evaluated by measuring serum creatinine (Scr) and blood urea nitrogen (BUN) levels. Inflammatory cytokines, oxidative stress markers, apoptosis-related proteins, fibrotic markers, NKD2, and METTL3 were detected by ELISA, qPCR, and Western blotting. Global m6A levels and NKD2 mRNA-specific m6A enrichment were measured by colorimetric assay and MeRIP-qPCR, respectively. Renal-specific METTL3-overexpressing mice were generated via lentivirus to validate target dependency. The role of the m6A reader IGF2BP3 was investigated using RIP-qPCR.
    RESULTS: HKSX significantly improved renal function and attenuated renal pathological injury, inflammation, oxidative stress, apoptosis, and fibrosis in UUO mice. Mechanistically, HKSX dose-dependently downregulated METTL3 expression, reduced both global renal m6A levels and NKD2 mRNA-specific m6A modification, and consequently inhibiting NKD2 overexpression. The protective effects of HKSX were largely abrogated in METTL3-overexpressing CKD mice. Furthermore, HKSX specifically inhibited the expression of the m6A reader IGF2BP3 and its binding to NKD2 mRNA.
    CONCLUSION: This study demonstrates that HKSX alleviates renal fibrosis by inhibiting METTL3, which reduces m6A modification on NKD2 mRNA, and by downregulating the stability reader IGF2BP3. These effects collectively decrease NKD2 mRNA stability and protein expression. These findings reveal a novel epitranscriptomic mechanism of HKSX and identify the METTL3/IGF2BP3/NKD2 axis as a key therapeutic pathway in CKD.
    Keywords:  Haikun Shenxi capsule; METTL3; NKD2; chronic kidney disease; m6A
    DOI:  https://doi.org/10.1155/mi/4365859
  38. Biochim Biophys Acta Mol Basis Dis. 2026 Aug 17. pii: S0925-4439(26)00286-3. [Epub ahead of print]1873(1): 168423
    Epitranscriptomic regulation of host-virus interactions.
    Simran Mehra, Sushant Phadnis, Ravi Kumar Y S, Anjali Singh, Bhupendra Verma.
      RNA chemical modifications, collectively termed the epitranscriptome, are now recognized as critical regulators of gene expression that influence host antiviral responses. These modifications are frequently co-opted by both RNA and DNA viruses to enhance their replication and evade immune detection. This review explores key RNA modifications, principal modifying enzymes, emphasizing how these modifications regulate mRNA stability, translation, and innate immune recognition of both host and viral RNAs. Furthermore, this review examines how viruses, including DENV, SARS-CoV-2, HIV-1, HCV, RSV, and HSV, manipulate host RNA modification systems. Overall, this review highlights the epitranscriptome as a dynamic interface in host-virus interactions and underscores its potential as a target for antiviral therapeutic development.
    Keywords:  Epitranscriptomics; Eraser; RNA modifications; Viruses; Writer
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168423
  39. Wiley Interdiscip Rev RNA. 2026 Jul-Aug;17(4):17(4): e70056
    Shaping Spliceosome Dynamics Through Protein Arginine Methylation.
    Sai Wu, Kelly Schneggenburger, Michael C Yu.
      Accurate removal of intervening intronic sequences from pre-mRNA is required for proper eukaryotic gene expression. This process, termed pre-mRNA splicing, is carried out by a spliceosome, a dynamic RNA-protein macromolecular machinery. Proteomic studies have shown that many spliceosomal components and associated factors harbor protein arginine methylation, a type of post-translational modification. These findings raise the question of how arginine methylation influences the process or outcome of pre-mRNA splicing. Although targeted studies have provided important molecular insights into how this modification regulates splicing protein subcellular localization, abundance, RNA/protein interactions, and snRNP biogenesis, much remains unknown, especially given the large number of methylated proteins identified that have known roles in regulating pre-mRNA splicing. In this review, we summarize current knowledge of how protein arginine methylation contributes to pre-mRNA splicing and discuss how this modification may help tune the structural and functional plasticity of the spliceosome.
    DOI:  https://doi.org/10.1002/wrna.70056
  40. J Mol Cell Biol. 2026 Aug 17. pii: mjag030. [Epub ahead of print]
    ALKBH3 is an NPM1-dependent nucleolar protein required for rRNA biogenesis and translation.
    Xixi Ma, Yuliang Huang, Hao Jin, Rui Zhang, Fangzhou Liu, Aifu Lin, Tianhua Zhou, Shanshan Xie.
      The nucleolus is a membraneless nuclear organelle formed by liquid-liquid phase separation and serves as the hub for ribosomal RNA (rRNA) transcription and ribosome assembly. Here, we identify ALKBH3, a Fe(II)/α-ketoglutarate-dependent dioxygenase, as a previously unrecognized nucleolar protein that colocalizes with the scaffold protein Nucleophosmin 1 (NPM1). Loss of ALKBH3 reduced nascent and precursor rRNA levels, impaired global protein translation, and suppressed cell proliferation. Although ALKBH3 lacked intrinsic LLPS capacity, it was recruited into NPM1 condensates via a direct interaction mediated by an N-terminal KRRRAR motif. Consistently, NPM1 knockdown diminished ALKBH3 nucleolar localization in cells, while in vitro assays demonstrated ALKBH3-NPM1 co-condensation. In zebrafish, alkbh3 knockdown decreased pre-rRNA abundance and caused dose-dependent developmental delays. Together, these findings establish ALKBH3 as an NPM1-dependent nucleolar client protein critical for rRNA biogenesis, protein synthesis, and vertebrate development.
    Keywords:  ALKBH3; Nucleophosmin 1 (NPM1); liquid–liquid phase separation (LLPS); nucleolus
    DOI:  https://doi.org/10.1093/jmcb/mjag030
  41. bioRxiv. 2026 Aug 04. pii: 2026.08.01.741249. [Epub ahead of print]
    EOLA1 functions in nucleotide salvage through deacetylating free N4-acetylcytidine.
    Sebastien Relier, Sarah Schiffers, Hamid Beiki, Maria Prigge, Nishu Tyagi, Cyrinne Achour, Ayush Raman, A Maxwell Burroughs, L Aravind, Shalini Oberdoerffer.
      RNA-based medicines rely on modified nucleotides to promote immune evasion and in vivo efficacy. Nucleotides generated from RNA degradation are either exported or recycled through metabolically favorable salvage pathways, though whether modified nucleotides are efficiently recycled remains unclear. N 4 -acetylcytidine (ac⁴C) is a naturally occurring modification in rRNA and tRNA that has shown promise in therapeutic mRNA applications. However, N 4 -acetylation impairs cytidine deamination, the first step in cytidine salvage. Here, we investigate the endogenous mechanisms that enable ac⁴C metabolism. Through sensitive sequence and structural analyses, we identify the uncharacterized human ASCH domain protein EOLA1 as a key ac⁴C deacetylase in nucleotide salvage. EOLA1 inactivation leads to free intracellular ac⁴C accumulation and increased cytotoxicity upon nucleotide export inhibition. While steady-state ac⁴C levels in cellular RNAs remain unchanged, EOLA1-dependent regulation of free ac⁴C is evident basally and is exacerbated by exogenous mRNA delivery. Proteomic analyses place EOLA1 in proximity to ribosomal proteins, adjacent to endogenous ac⁴C sources. In vitro assays confirm EOLA1 specificity for ac⁴C, and structural analysis reveals a narrow nucleotide-binding pocket consistent with mononucleotide selectivity. These findings identify EOLA1 as a bona fide ac⁴C eraser and uncover a previously unrecognized pathway for recycling modified nucleotides with relevance to therapeutic RNA design.
    DOI:  https://doi.org/10.64898/2026.08.01.741249
  42. Front Vet Sci. 2026 ;13 1906705
    Global transcriptomic response of Malassezia pachydermatis isolates under ketoconazole-induced stress.
    Marianna Domán, Enikő Wehmann, László Makrai, Enikő Fehér, Tibor Magyar.
      Malassezia pachydermatis is an opportunistic yeast associated with otitis externa and dermatitis in dogs. Despite reduced susceptibility to azole antifungals has increasingly been reported in M. pachydermatis, the molecular mechanisms underlying azole stress responses in this species remain poorly understood. In this study, we investigated the global transcriptional response of two M. pachydermatis isolates with different ketoconazole minimum inhibitory concentration values following short-term ketoconazole exposure. Ketoconazole treatment resulted in slightly distinct transcriptional profiles in the two isolates. In isolate 12372, 80 genes were significantly upregulated and 120 were downregulated, whereas isolate 12693 showed 158 upregulated and 211 downregulated genes. Both isolates exhibited significant upregulation of genes involved in ergosterol biosynthesis, including ERG3, ERG5, ERG11, ERG24, and ERG25 suggesting a conserved compensatory response to azole-mediated disruption of sterol metabolism. In isolate 12372, genes associated with ribosome biogenesis was predominantly downregulated, indicating reduced protein synthesis and growth-related activity. In isolate 12693, ketoconazole primarily suppressed genes involved in amino acid biosynthesis, and central carbon metabolism; and upregulated genes associated with ubiquitin ligases, RNA polymerase II regulators, and RNA-binding proteins. Notably, genes encoding ABC transporter-associated efflux pumps were not transcriptionally induced under the tested conditions. Our results provide a comprehensive transcriptomic profile of M. pachydermatis under azole stress, demonstrating that the yeast employs diverse metabolic strategies to enter a decelerated growth state and offer a good basis for identifying future therapeutic targets to combat azole resistance.
    Keywords:  Malassezia pachydermatis; RNA-sequencing; differentially expressed genes; ketoconazole; stress response
    DOI:  https://doi.org/10.3389/fvets.2026.1906705
  43. Bone Res. 2026 Aug 17. pii: 86. [Epub ahead of print]14(1):
    Biomolecular condensates as dynamic regulators of musculoskeletal homeostasis, disease, and therapeutic challenges.
    Qichen Miao, Ruiqi Gao, Mingyang Huang, Guoqing Wang, Wengang Wang, Ming Luo.
      Biomolecular condensates are membraneless assemblies that concentrate proteins, nucleic acids, and other biomolecules into dynamic cellular compartments. Liquid-liquid phase separation (LLPS) is one important route by which such condensates form, particularly when multivalent interactions generate liquid-like, reversible assemblies. However, not every condensate or disease-associated assembly should be explained solely by LLPS. In the musculoskeletal system, condensates have been linked to transcription, signal transduction, RNA metabolism, stress responses, tissue development, homeostasis, and mechanoadaptation. Genetic mutations, altered post-translational modifications, and environmental stress can disturb these assemblies, but the evidence does not always establish whether condensates are causal drivers of disease or downstream responses to injury. This review examines how biomolecular condensates and LLPS-related mechanisms have been implicated in osteoporosis, osteoarthritis, skeletal muscle atrophy, bone and soft tissue sarcomas, and neuromusculoskeletal diseases. We focus on the strength of the available evidence, distinguish correlative observations from causal mechanisms where possible, and discuss how condensates may connect non-coding genetic variants, mechanical cues, metabolic signals, and disease phenotypes. We also assess the translational potential and limitations of condensate-based biomarkers, therapies that target pathological condensates, and phase-separation-inspired delivery systems. A central message is that biomolecular condensates offer a useful framework for musculoskeletal biology, but clinical translation will require disease-specific targets, human-relevant models, selective delivery, and rigorous tests of causality.
    DOI:  https://doi.org/10.1038/s41413-026-00578-6
  44. bioRxiv. 2026 Aug 03. pii: 2026.07.31.742119. [Epub ahead of print]
    Subcellularly Resolved 3D Translatome in Mouse Oocytes and Early Embryos.
    Jingyi Ren, Seth Furniss, Chengjie Zhou, Haowen Zhou, Yota Hagihara, Xiao Wang, Yi Zhang.
      Spatial patterning of mRNA translation is a fundamental process in early embryogenesis. Existing RNA translation profiling methods lack subcellular spatial resolution at the single-molecule level, limiting our understanding of spatial RNA biology in embryogenesis. To address this, we profiled the spatial translatome of intact mouse embryos at near-genomic scale by adapting RIBOmap and incorporating multiplexed organelle staining. In oocytes, 2-cell and 4-cell embryos, we systematically analyzed RNA translation across three spatial scales: organelle, subcellular, and intercellular. We found that functionally related genes exhibit spatially and temporally controlled translation patterns near distinct organelles. Using Harmonics, a graph signal processing framework, we demonstrate that embryo asymmetry emerges at the first cell division and is amplified at later stages. This work paves the way for comprehensively investigating the fundamental spatial post-transcriptional regulation at the earliest moments of mammalian life.
    DOI:  https://doi.org/10.64898/2026.07.31.742119
  45. Plant Physiol Biochem. 2026 Aug 18. pii: S0981-9428(26)00652-2. [Epub ahead of print]238 111666
    Waterlogging stress reshapes epigenetic regulation of gene expression in Brassica napus.
    Jiangfeng Li, Fanzhe Kong, Jianbo Wang.
      Waterlogging stress significantly impairs early development and yield in Brassica napus, yet the underlying epigenetic regulatory mechanisms remain poorly understood. We applied a multi-omics strategy integrating RNA-seq, WGBS, and ChIP-seq to dissect multi-layered regulatory dynamics during waterlogging stress and recovery. We found that waterlogging stress globally repressed gene expression and enhanced expression divergence between homoeologous genes of the two subgenomes. Transposable element (TE) activation, together with dynamic epigenetic changes, is associated with altered expression of neighboring genes under waterlogging stress. This study provides novel insights into the multilayered epigenetic regulation of waterlogging responses in a polyploid crop and highlights the regulatory potential of TEs in stress adaptation.
    Keywords:  Brassica napus; DNA methylation; Epigenetic regulation; Histone modification; Homoeologous expression bias; Transposable element; Waterlogging stress
    DOI:  https://doi.org/10.1016/j.plaphy.2026.111666
  46. Biosci Biotechnol Biochem. 2026 Aug 19. pii: zbag126. [Epub ahead of print]
    Sorbic acid prevents tunicamycin-induced endoplasmic reticulum stress and Ire1-Hac1 pathway activation in Saccharomyces cerevisiae.
    Yuki Namekata, Yukio Kimata, Shingo Izawa.
      Sorbic acid is a widely used food preservative recognized for its potent fungistatic effects, yet its specific mechanisms of action remain poorly understood. While investigating its effects on yeast organelles, we found that fungistatic concentrations of sorbic acid do not disturb homeostasis within the endoplasmic reticulum (ER). This contrasts with acetic acid, which induces ER stress despite having a similar dissociation constant, suggesting that ER disturbance is unlikely to be central to the fungistatic mechanism of sorbic acid. Unexpectedly, we discovered that sorbic acid prevents the induction of ER stress and the unfolded protein response (UPR) by tunicamycin. Sorbic acid abrogates activation of the Ire1-Hac1 pathway when administered prior to or during tunicamycin treatment, although it cannot suppress an already-induced UPR. These findings provide new insights into the physiological effects of sorbic acid on the yeast ER and the mechanism of action of tunicamycin.
    Keywords:   Saccharomyces cerevisiae ; endoplasmic reticulum stress; sorbic acid; tunicamycin; unfolded protein response
    DOI:  https://doi.org/10.1093/bbb/zbag126
  47. bioRxiv. 2026 Aug 06. pii: 2026.08.02.742296. [Epub ahead of print]
    Mapping genome-wide RNA-RNA and RNA-DNA interactions in nuclear hubs of male and female Drosophila cells.
    Sarah Gunasekera, Megan Carlson, Mukulika Ray, Erica Larschan.
      Nuclear bodies are nucleoprotein complexes with established functions that target chromatin at specific locations and regulate specific RNA processing functions, thereby influencing gene expression. However, the mechanisms that define how nuclear bodies are targeted to specific locations within the genome where they function remain poorly understood. One significant challenge is capturing and understanding the multiple cell-specific interactions occurring in these complexes, arising from RNA components interacting with each other and with DNA and nucleic acid-binding proteins within the context of the nucleus's three-dimensional organization. Mapping these interactions is critical for elucidating mechanisms such as RNA splicing, a key driver of cell-specific transcript diversity. Here, we use RNA-DNA Split Pool Recognition of Interactions by Tag Extension (RD-SPRITE) to characterize, for the first time, sex-specific RNA-RNA and RNA-DNA interactions in Drosophila S2 (male) and Kc (female) cells. We determined the sex-specific RNA-RNA interaction map within the nucleus and, using RNA-DNA interaction data, pinpointed the target loci of various RNA molecules, including small nuclear RNAs (snRNAs), which are core components of the spliceosome-a ribonucleoprotein complex involved in RNA splicing. Based on RNA-RNA interaction data, we also identified novel long non-coding RNAs that may regulate splicing. Furthermore, we investigated the role of transcription factor (TF) CLAMP in sex-specific targeting of the spliceosome. We generated RD-SPRITE datasets in the presence and absence of CLAMP, a key TF involved in dosage compensation, sex-specific RNA splicing, and chromatin organization. We determined that CLAMP regulates global changes in spliceosomal interactions with chromatin, inhibits aberrant snRNA interactions, and regulates sex-specific interactions of RNAs involved in splicing function. Additionally, our dataset provides a valuable resource for investigating additional processes, such as miRNA-mediated silencing, nucleolar functions of snoRNAs, and Cajal body functions of scaRNAs, among others. To facilitate broad community use, we have developed a computational platform, "FlySprite," that enables Drosophila researchers to explore sex-specific RNA-RNA interactions, as well as DNA targets of RNA clusters, through a user-friendly interface.
    DOI:  https://doi.org/10.64898/2026.08.02.742296
  48. Front Cell Dev Biol. 2026 ;14 1898983
    Heat shock proteins in male infertility: recent advances and clinical implications.
    Zhongnan Wu, Wanting Zhang, Ruqi Han, Huiyu Ping, Linhui Xia, Haoran Ding, Jinxiang Yuan, Xiaomei Wang, Qin Qin.
      The decline in male sperm quality has become a global concern for male reproductive health. Research indicates that heat stress is an important external factor that contributes to male infertility, potentially promoting germ cell apoptosis, disrupting redox balance, and affecting proteostasis. Recently, a growing body of research has demonstrated an association between heat stress-related proteins and male infertility. Heat shock proteins (HSPs) and their upstream transcription factors, known as heat shock factors (HSFs), constitute the core molecular system through which cells respond to heat stress. The main heat-shock protein families, including HSPA1, HSPA2, HSP90, HSP60, and small HSPs Small Heat Shock Proteins, play pivotal regulatory roles in spermatogenesis. These protein families influences the balance between germ cell repair and cell death by regulating proteostasis, oxidative homeostasis, and cell survival. The dysregulation of this system may represent an important molecular basis for heat stress-induced male infertility. This review focuses on the pathophysiological process of heat stress-induced male infertility, summarizes the potential mechanisms by which heat stress and heat stress-related proteins contribute to male infertility, and proposes a dynamic model of HSP systemic responses under heat stress. The current progress in the diagnosis and treatment of heat stress-related male infertility is summarized to provide a theoretical basis for further elucidating its pathogenesis, improving diagnostic accuracy, and guiding the developing of targeted therapeutic strategies.
    Keywords:  heat shock proteins; heat shock transcription factors; heat stress; male infertility; spermatogenesis
    DOI:  https://doi.org/10.3389/fcell.2026.1898983
  49. Anal Chem. 2026 Aug 18. 98(32): 23819-23826
    Circular RNA Translation Modulation via Small Ligand-Mediated Protein Stabilization.
    Hua Li, Kehui Xin, Li-Juan Tang, Fenglin Wang, Jian-Hui Jiang.
      Circular RNAs (circRNAs) have emerged as a promising platform for RNA-based therapeutics, ascribed to their excellent stability and prolonged protein translation capacity. However, modulation of circRNA translation remains a great challenge. Here, we develop a new chemically regulated circRNA translation system based on small ligand-induced stabilization of RNA-binding proteins (RBPs). The system is engineered by incorporating RNA motifs into an internal ribosomal entry site and fusing RBPs with small ligand-stabilized conditional proteins. We show that this design allows small ligand-modulated translation of circRNAs with a wide dynamic range and dose dependency. It is demonstrated that this strategy is modular and versatile to different RBPs and small-ligand-stabilized conditional proteins. We further employ this strategy to control the translation of functional proteins, including a guanine nucleotide exchange factor for modulating signaling pathways and a bispecific engager for regulating T cell activities. This system is highly modular and versatile, highlighting its great potential for basic research and therapeutic applications.
    DOI:  https://doi.org/10.1021/acs.analchem.6c03443
  50. Curr Diabetes Rev. 2026 Jul 31.
    Mechanisms and Current Therapeutic Targets of Podocyte Damage in Diabetic Kidney Disease.
    Bilge Karatoy Erdem.
       INTRODUCTION: Diabetic Kidney Disease (DKD) is a leading cause of end-stage kidney disease, and podocyte injury is a pivotal driver of albuminuria, glomerulosclerosis, and progressive loss of kidney function.
    METHODS: A targeted narrative search of PubMed/MEDLINE, Scopus, and Web of Science was performed, primarily covering 2015-2025 and supplemented by seminal earlier studies. Inclusion criteria prioritized human studies, randomized and translational studies, and mechanistic work directly addressing podocyte injury or podocyte-relevant therapeutic effects in DKD. Studies with limited mechanistic or translational relevance were excluded or deprioritized.
    RESULTS: Diabetic metabolic and hemodynamic stress activates AGE/PKC/RAAS signaling and downstream TGF-β/Smad, NF-κB, PI3K/Akt/mTOR, TRPC6-Ca2+, and mitochondrial stress pathways. These pathways converge on slit diaphragm disruption, actin cytoskeletal remodeling, impaired autophagy, ER stress, apoptosis, detachment, and progressive podocyte depletion. Current standard-of-care therapies, including RAAS blockade, SGLT2 inhibitors, GLP-1 receptor agonists, and finerenone, provide partial podocyte-relevant renoprotection, whereas endothelin receptor antagonists, anti-TGF-β/CTGF approaches, JAK/STAT inhibitors, TRPC6 blockade, redox-targeted therapies, RNA-based strategies, and extracellular vesicle approaches remain at different stages of clinical readiness.
    DISCUSSION: The available evidence supports a layered model in which systemic metabolic and hemodynamic therapies reduce upstream stress, while emerging podocyte-directed strategies aim to stabilize cytoskeletal, slit diaphragm, inflammatory, fibrotic, calcium, and organelle-stress pathways. Combination therapy is biologically plausible but should be guided by albuminuria, eGFR, cardiometabolic phenotype, tolerability, and validated podocyte-related biomarkers.
    CONCLUSION: A podocyte-centered framework that links mechanisms, biomarkers, evidence tiering, and patient stratification may improve translation of targeted and combination strategies. However, clinical implementation requires stronger biomarker validation, optimized human-relevant models, and long-term safety and outcome data.
    Keywords:  Diabetic kidney disease; SGLT2 inhibitor; TGF-β/Smad; autophagy; finerenone.; mitochondrial dysfunction; oxidative stress; podocyte damage
    DOI:  https://doi.org/10.2174/0115733998492007260723100211
  51. Methods Enzymol. 2026 ;pii: S0076-6879(26)00158-8. [Epub ahead of print]733 55-79
    Chromatin immunoprecipitation assay for analyzing histone H3-mediated regulation of copper homeostasis.
    Sakshi Singh, Rakesh Kumar Sahu, Raghuvir Singh Tomar.
      Histone tails undergo various post-translational modifications that aid in recruiting effector proteins involved in diverse transcriptional responses. Our previous work explored the role of histone H3 N-terminal residues and their modifications on the transcriptional regulation of the CUP1 metallothionein gene during cellular copper stress. To pinpoint critical histone residues, we used complementary methods, including growth assays and gene expression kinetics. We screened a library of synthetic histone H3 and H4 mutants for copper response defects by assessing their sensitivity to copper stress and quantifying CUP1 transcript levels via real-time PCR. We further investigated the mechanisms of impaired CUP1 transcription by assessing the recruitment of Ace1, a copper-sensing transcription factor that activates CUP1 in response to high intracellular copper, and of TATA-binding protein (TBP), using chromatin immunoprecipitation (ChIP) assays. Our results showed that mutations in the H3 N-terminal tail impair the recruitment of Ace1 and TBP to the CUP1 promoter, causing defects in its induction. Collectively, these findings highlight the significance of histone residues and their modifications in regulating metal homeostasis. This chapter outlines the methods used to study histone-mediated regulation of copper homeostasis, with a focus on the chromatin immunoprecipitation assay.
    Keywords:  Ace1; Chromatin immunoprecipitation; Copper homeostasis; Cup1; Histone modification; Metallothionein; TBP; Transcription factor; Transcription regulation
    DOI:  https://doi.org/10.1016/bs.mie.2026.05.030
  52. Comp Biochem Physiol Part D Genomics Proteomics. 2026 Aug 15. pii: S1744-117X(26)00241-8. [Epub ahead of print]60 101982
    Genome-wide characterization of heat shock protein genes reveals thermal stress-responsive candidates in Litopenaeus vannamei.
    Aminah A Barqawi.
      Heat shock proteins (HSPs) are conserved molecular chaperones involved in protein folding, refolding, aggregation prevention, and degradation of damaged proteins. However, the genomic organization and thermal responsiveness of HSP genes in the Pacific white shrimp (Litopenaeus vannamei) remain incompletely understood. Here, we performed a genome-wide analysis of the HSP gene family and examined its phylogenetic relationships, structural features, duplication patterns, sequence variation, interaction networks, and transcriptional responses to acute heat stress. A total of 34 HSP genes were identified and classified into the HSP90, HSP70, HSP40/DNAJ, HSP60, and small HSP families. Phylogenetic, motif, gene structure, synteny, and subcellular localization analyses revealed evolutionary conservation and structural diversification among family members. Three duplicated gene pairs were identified, comprising two segmental duplications and one tandem duplication. All pairs exhibited Ka/Ks ratios below 1, consistent with purifying selection of varying strength. Sequence analysis identified 295 nonsynonymous single-nucleotide polymorphisms, of which 12 were consistently predicted to be deleterious by multiple algorithms. Protein-protein interaction analysis indicated enrichment of protein-folding and cellular stress-response functions. RT-qPCR analysis showed significant induction of HSPA4, HSP90AA1, TRAP1, BiP, and DNAJA1 after 6, 12, and 24 h of exposure to 34 °C, whereas DNAJC3 was significantly induced only at 12 h. All six genes reached their highest transcript abundance at 12 h. These findings may provide a genomic framework for HSP genes in L. vannamei and identify candidate genes and variants associated with thermal stress responses.
    Keywords:  Comparative genomics; Gene duplication; Molecular chaperones; Nonsynonymous variants; Shrimp aquaculture
    DOI:  https://doi.org/10.1016/j.cbd.2026.101982
  53. Front Immunol. 2026 ;17 1795910
    Heat shock proteins in farmed aquatic animals: advancing animal health and welfare management through building resilience.
    Ppsk Patabandi, Parisa Norouzitallab, Dipesh Debnath, Rishikesh Subhashrao Dalvi, Amit Kumar Sinha, Mazlan Bin Abd Ghaffar, Yeong Yik Sung, Kartik Baruah.
      Aquaculture is vital for global food security. Intensification of farming practices has compromised the welfare of farmed aquatic animals and increased disease outbreaks. Conventional treatments, such as antibiotics, face growing challenges due to antimicrobial resistance and environmental concerns. Consequently, there is a pressing need for sustainable, welfare-oriented disease management strategies in aquaculture animals. One promising solution involves heat shock proteins belonging to the 70-kDa family [Hsp70s], which provide several health benefits. Hsp70s are evolutionarily conserved proteins produced constitutively or induced in response to various conditions, where they function as molecular chaperones to perform immune-enhancing functions vital for cellular survival during both stable and stressful conditions. Recent advances have highlighted the role of Hsp70s and their inducers in promoting disease tolerance by building resilience and improving overall animal welfare in aquaculture systems. This review integrates current knowledge on the role of Hsp70s in fish stress physiology and welfare and critically evaluates their potential applications as sustainable tools for improving fish health, enhancing welfare outcomes, and controlling disease outbreaks in aquaculture systems.
    Keywords:  diseases; heat shock protein; infection stress; robustness; sustainable aquaculture
    DOI:  https://doi.org/10.3389/fimmu.2026.1795910
  54. Cell Chem Biol. 2026 Aug 20. pii: S2451-9456(26)00283-7. [Epub ahead of print]33(8): 1071-1073
    Allosteric rewiring of mitochondrial stress signaling through Miro1.
    Layla Drwesh, Julia C Fitzgerald.
      In this issue of Cell Chemical Biology, Chandra and colleagues1 demonstrate that allosteric modulation of the mitochondrial protein Miro1 can selectively reprogram mitochondrial stress signaling. Chemical targeting of a single molecular hub can produce distinct responses in disease-relevant cell types, despite acting within a broadly conserved stress pathway.
    DOI:  https://doi.org/10.1016/j.chembiol.2026.07.011
  55. Redox Biol. 2026 Aug 16. pii: S2213-2317(26)00343-5. [Epub ahead of print]96 104344
    Chronic nitric oxide mediates dual-layer gene regulation through mRNA m6A positional remodeling and parallel transcriptional reprogramming.
    Sara Shayan, Hannah Petraitis Kuschman, Christopher G Kevil, Douglas D Thomas.
      Nitric oxide (NO) is a pleiotropic free radical that functions as a master regulator of gene expression, and its sustained production within the tumor microenvironment reshapes the epitranscriptomic state of cancer cells. We previously demonstrated that NO inhibits the m6A mRNA demethylases FTO and ALKBH5 through dinitrosyliron complex formation while leaving the methyltransferase METTL3 intact, a demethylase-specific perturbation that increases global m6A on mRNA. Here, integrating m6A-RIP-seq and RNA-seq from triple-negative breast cancer cells, we show that chronic NO does not produce the uniform hypermethylation anticipated from demethylase inhibition. Instead, it redistributes m6A on mRNA, enriching the 5'UTR and coding sequence while depleting the 3'UTR and departing from the canonical stop-codon and 3'UTR topology. We found that the position of m6A, rather than its intensity or mere presence, shapes the outcome, in part by determining which reader protein is predicted to recognize it. In parallel, NO drives a canonical NF-κB and inflammatory transcriptional program. The transcriptional program is independent of the m6A methylome in both which genes respond and how strongly they respond, ruling out a linear methylome-to-transcriptome cascade; even so, m6A position remains associated with the direction of change among responding transcripts. The 3'UTR is the primary site of m6A loss and shows a suggestive computational link to miRNA-mediated regulation. Sense-antisense coordination reinforces the transcriptional response without bridging the two programs. These findings demonstrate that NO not only increases m6A abundance, but it also rewrites the m6A positional code, establishing spatial reprogramming of the epitranscriptome as a previously unrecognized mode of gene regulation.
    Keywords:  Epitranscriptome; FTO; N(6)-methyladenosine; Nitric oxide; Triple-negative breast cancer; mRNA
    DOI:  https://doi.org/10.1016/j.redox.2026.104344
  56. Mol Cell. 2026 Aug 17. pii: S1097-2765(26)00510-1. [Epub ahead of print]
    Pervasive noise in human pre-mRNA splice site selection.
    Eraj S Khokhar, Kaitlyn Brokaw, Zachary J Kartje, Ye Liu, Valeria Sanabria, Nida Javeed, Ayush Kumar, Ezequiel Calvo-Roitberg, Jonathan K Watts, Athma A Pai.
      RNA splicing has historically been thought to be highly efficient and accurate, with little opportunity for deviation from regulated alternative splicing. This dogma has been challenged by recent observations that biological noise may contribute substantially to transcriptome diversity. However, quantitative understanding of stochastic splicing variation is challenging because these transcripts are likely subject to rapid degradation. Here, we use deep sequencing across RNA compartments to track splicing intermediates in human cells and see abundant cryptic splicing associated with genomic features that promote splicing noise. We observe pervasive usage of low-fidelity splice sites, likely due to stochasticity in recruitment or binding of the spliceosome. These sites are turned over quickly and show evidence for nuclear and cytoplasmic degradation, suggesting widespread surveillance and rapid quality control of non-productive transcripts. Our findings provide insights into the propensity for error in RNA processing mechanisms and regulation of alternative splice sites across a gene.
    Keywords:  RNA splicing; RNA-seq; genomics; systems biology
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.024
  57. Crit Rev Oncol Hematol. 2026 Aug 20. pii: S1040-8428(26)00439-7. [Epub ahead of print] 105552
    KDM4A-Driven Epigenetic Reprogramming as a Central Nexus Linking Metabolic Adaptation, Immune Remodeling, and Therapy Resistance in Cancer.
    Xin Tang, Yunhan Zhao, Xianghai Yang, Jianrong Cheng.
      Cancer progression and treatment failure are driven not only by genetic alterations but also by the remarkable capacity of tumor cells to adapt to metabolic stress, immune surveillance, and therapeutic pressure. Epigenetic plasticity provides a rapid and reversible mechanism that enables such adaptation. Lysine demethylase 4A (KDM4A), a JmjC-domain-containing histone demethylase targeting H3K9me3 and H3K36me3, has emerged as a central epigenetic regulator of cancer adaptability. Recent studies reveal that KDM4A functions beyond a conventional chromatin modifier and instead acts as an epigenetic hub integrating microenvironmental cues, metabolic signals, and stress responses. Through transcriptional and post-translational regulation, KDM4A coordinates chromatin remodeling programs that support metabolic adaptation, including amino acid utilization, mitochondrial quality control, lipid metabolism, and resistance to ferroptosis. In parallel, KDM4A reshapes tumor-immune interactions in a state-dependent manner. In proliferative and stress-tolerant tumor states, KDM4A-associated chromatin remodeling may support metabolic adaptation, replication-stress tolerance, and immune exclusion. By contrast, under conditions of impaired mitochondrial quality control and sustained metabolic stress, KDM4A can promote tumor-cell senescence and enhance responsiveness to immune checkpoint blockade. These divergent outcomes indicate that the consequences of KDM4A activity are determined by the interaction between substrate- and locus-specific chromatin remodeling and the cellular, metabolic, and therapeutic context in which it occurs. KDM4A-driven epigenetic reprogramming also underlies multiple mechanisms of therapy resistance, encompassing enhanced DNA damage repair capacity, metabolic buffering via mitophagy, and lineage plasticity-mediated therapy escape. These adaptive strategies allow cancer cells to survive therapeutic stress without reliance on additional genetic mutations, contributing to disease progression and poor clinical outcomes. In this review, we synthesize current mechanistic and translational evidence to present a unified framework in which KDM4A links metabolic adaptation, immune remodeling, and therapy resistance. We further discuss therapeutic opportunities, rational combination strategies, and the emerging biomarker potential of KDM4A-centered pathways, highlighting their relevance for precision oncology.
    Keywords:  Epigenetic reprogramming; KDM4A; Metabolic adaptation; Therapy resistance; Tumor immune microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105552
  58. RNA. 2026 Aug 20. pii: rna.080914.125. [Epub ahead of print]
    Seed pairing between a small regulatory RNA and target mRNA determines cleavage by a RNase E with a minimal C-terminal scaffold.
    Carlos Daniel Vega Valle, Karine Prevost, David Lalaouna, Eric Masse.
      Small regulatory RNAs (sRNAs) can specifically bind to their target mRNAs to inhibit their expression, either by promoting degradation or by blocking translation. However, the molecular determinants that select which repression mode an sRNA employs remain poorly understood. To investigate this, we used the model target mRNA hdeD, which is repressed by two sRNAs, CyaR and RprA, both of which use distinct modes of repression. Whereas CyaR promotes the target mRNA hdeD degradation, the sRNA RprA specifically blocks hdeD translation initiation, leaving hdeD mRNA intact. We found that mutating two nucleotides in the seed pairing region of RprA with hdeD is sufficient to switch its mode of repression from translation inhibition to degradation by recruiting RNase E. We investigated this further by using various RNase E deletion mutants of the C-terminal domain (CTD). Among these was a RNase E mutant deleted to contain a minimal C-terminal scaffold (rne 701), a form which typically fails to promote sRNA-induced mRNA degradation. Our data indicated that even with a minimal scaffold, the mutated RprA sRNA still promoted hdeD mRNA degradation, whereas the native sRNA CyaR could not. Our data suggested that the mutated RprA sRNA relies primarily on the arginine-rich RNA-binding (ARRBD) domain of RNase E to induce target mRNA hdeD degradation. This suggests that the mutated RprA sRNA requires fewer components of the CTD of RNase E and RNA degradosome to induce target mRNA degradation.  .
    Keywords:  Class II sRNAs; CyaR; Hfq; RNase E; RprA
    DOI:  https://doi.org/10.1261/rna.080914.125
  59. bioRxiv. 2026 Aug 01. pii: 2026.07.31.742112. [Epub ahead of print]
    Combinatorial sequence elements fine-tune mitochondrial protein import to facilitate dual localization.
    Youmian Yan, Lianjie Wei, Thomas Schodl, Keri-Lyn Kozul, Maria Behrens, Stephen P Plassmeyer, Alex S Holehouse, Natalie M Niemi.
      The dual targeting of mitochondrial proteins regulates a host of cellular processes, including metabolism, cofactor biosynthesis, mitophagy, and stress responsiveness. Despite this importance, the mechanisms by which proteins dually localize are incompletely defined. Here, we identify multiple sequence elements that compromise the matrix localization of the phosphatase PPTC7 to facilitate its accumulation at the outer mitochondrial membrane (OMM), where it regulates mitophagy. We find that PPTC7 has a moderately 'weak' presequence, but this feature is insufficient to promote dual targeting of a generic cargo protein. Instead, our data suggest that a recently evolved glycine stretch decreases the helical potential of the PPTC7 presequence, weakening its import efficiency in vitro and in cells. Deletion of these glycine residues improves PPTC7 in vitro import and enrichment within the mitochondrial matrix, but only partially suppresses PPTC7-mediated regulation of mitophagy at the OMM. These data suggested additional elements may contribute to PPTC7 dual localization, including its mature phosphatase domain which has robust thermal stability and becomes further stabilized to an import-incompetent state upon binding to its requisite enzymatic co-factor manganese. Simultaneous increases in presequence strength and denaturation of the PPTC7 phosphatase domain are required to promote import in vitro, underscoring the multifactorial challenges associated with its matrix targeting. These data suggest that sequence-specific features can work combinatorially to impart dual-localization capacity to mitochondrial proteins, enabling functions across cellular compartments.
    DOI:  https://doi.org/10.64898/2026.07.31.742112
  60. Curr Opin Struct Biol. 2026 Aug 18. pii: S0959-440X(26)00144-2. [Epub ahead of print]101 103362
    A new dimension in protein-RNA interface prediction: Integrating protein language models and geometric deep learning.
    Rozeena Arif, Alfredo Castello.
      RNA-binding proteins (RBPs) are essential across biology, from viruses to complex multicellular organisms. They regulate gene expression and cellular responses, making RNA recognition central to understanding health and disease. Biochemical, biophysical, and structural studies have defined core principles of RNA binding, but recent RNA interactome surveys have expanded the RBP repertoire and revealed many noncanonical RNA-binding regions. This diversity demands highly scalable predictive methods. Here, we review machine learning predictors built on protein language models and structure-aware representations. These approaches improve generalisability, reduce reliance on deep evolutionary information, and enable proteome-scale prediction of RNA-binding residues, providing a route to map and interpret the molecular logic of protein-RNA interactions.
    DOI:  https://doi.org/10.1016/j.sbi.2026.103362
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