bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–10–11
63 papers selected by
Cédric Chaveroux, CNRS
  1. Dysregulated mRNA Translation in Alzheimer's Disease: Mechanisms, Therapeutic Opportunities, and Challenges for Clinical Translation.
  2. RSL24D1 links ribosome biogenesis to p53 activation in melanoma.
  3. Ribosome remodeling drives translation adaptation during viral infection and cellular stress.
  4. Oligo(uridine) tailing and exonucleolytic decay drive 40S ribosome degradation in response to stress.
  5. Temozolomide Induces Aberrant RNA Alkylation and Widespread Translational Repression.
  6. Protein homeostasis and inter-organellar signaling under salt stress.
  7. The Partition Code: How RNA Modifications Set the Address of Transcripts Among Membraneless Compartments: Covalent RNA Marks Set a Measurable, Reversible Spatial Address Among Membraneless Compartments-A Variable to Perturb, Not Just Observe.
  8. You are what you eat and translate: Feeding the code to fight cancer and viruses.
  9. Tyrosine phosphorylation unfolds nucleophosmin and disrupts its integration into the nucleolus.
  10. BR-bodies link RNA homeostasis to stress tolerance and intracellular fitness in Brucella.
  11. Deletion of the gene for a cyanobacterial ribosome-associated protein affects the carbon/nitrogen metabolism.
  12. Protein damage and repair in aging: mechanisms, homeostasis and disease.
  13. Synaptic Proteostasis in Health and Disease.
  14. NET1 mRNA localization to the midbody is required for Arp2/3-dependent initiation of mitotic abscission.
  15. Pyrrolysine supply and demand shapes the translational landscape in Methanosarcina acetivorans.
  16. Real-time single-molecule imaging in zebrafish embryos uncovers noncanonical translation.
  17. RNA N4-acetylcytidine modification in health and cancer: molecular mechanisms, cellular plasticity, and therapeutic opportunities.
  18. Emerging mechanisms of ATG8-independent non-canonical autophagy.
  19. Expression and role of HSPA5 in environmental toxin-induced neurological disorders.
  20. YTHDF2 drives malignant progression in cutaneous melanoma through m⁶A-dependent HMOX1-mediated ferroptosis.
  21. Rescue of ribosomal protein bL27 in Streptococcus pneumoniae TIGR4 by an alternate protease.
  22. Disruption of dnaK results in transcriptional reprogramming of biofilm-associated pathways in Clostridioides difficile.
  23. Allele-resolved monosome and polysome sequencing identifies cis-variants affecting mRNA translation.
  24. Dual Roles of p53-Related Protein Kinase in Cytoskeletal Remodeling and Translational Control.
  25. Functional roles for viral RNA ribosylation in mammalian cells.
  26. Site-specific N6-methyladenosine fine tunes CTCF/cohesin-defined enhancer-promoter interactions and oncogenic transcription program.
  27. METTL3-mediated m6A modification of PARP2 accelerates hepatocellular carcinoma progression.
  28. Responses to endoplasmic reticulum stress at a glance.
  29. Cold-sensitive chloroplast development: advances from chloroplast ribosome-deficient mutants.
  30. 40S ribosome remodeling triggers 18S rRNA U-tailing and DIS3L2-dependent decay.
  31. Active transcriptome remodeling underlies antimony-induced drug tolerance in persister-like Leishmania parasites.
  32. Tau phosphorylation from neuronal adaptation to Alzheimer's disease.
  33. Novel hybrid salicylaldehyde-sulfonamide schiff bases elicit an ISR-associated transcriptomic response and suppress cancer cell survival.
  34. GlRac regulates an ATG8-independent autophagy-like pathway in Giardia lamblia.
  35. Optimization of Circle-Seq improves transcription error profiling and transcriptome representation.
  36. Precision engineering of upstream open reading frames for translational regulation and crop improvement.
  37. tRF-3021a Promotes Apoptosis Resistance and Global Protein Synthesis in Cancer Cell Lines.
  38. VAEBAC: A representation-learning framework for proteome-scale prediction of amyloidogenic proteins and functional stratification of nucleic-acid-binding proteins.
  39. ZNF121 recruits YTHDF2 to modulate mRNA stability.
  40. Establishing the molecular basis for MDA5 mutation-linked autoimmunity.
  41. SUMOylation and palmitoylation in metastatic prostate cancer: A compartment-based framework for nuclear and membrane adaptation.
  42. Differences of oxidative damage in the brain of short- and long-lived Nothobranchius furzeri strains.
  43. Starving but surviving: a new RNA switch rewires parasite metabolism.
  44. Mitochondrial YME1L Restrains GRP75-Dependent ISR Activation to Prevent Podocyte Senescence in Diabetic Kidney Disease.
  45. METTL3-Associated FOXD1 Regulation Promotes Lung Squamous Cell Carcinoma Progression: A Multimodel Experimental Approach.
  46. Preferential G3BP1-induced condensation of DNA-RNA mixtures from stress granules over RNA or double-stranded DNA.
  47. A catalog of mRNAs transferred from males to females during mating in Drosophila arizonae and D. mojavensis.
  48. Adipocyte-derived exosomal ANGPTL2 promotes beta cell dysfunction via the EIF2α/ATF4/CHOP stress pathway in mice.
  49. NMR assignments and secondary structure analysis of the human 5MP1 C-terminal domain.
  50. PNLDC1 deadenylase affects translational rate and cell proliferation in mESCs.
  51. Life without cytoplasm: sperm sustain protein production utilizing cytoplasmic droplets and mitochondria as translational apparatuses.
  52. Molecular remodelling of Cryptococcus neoformans during adaptation to host temperature.
  53. From chromatin to proteostasis: multilevel gene regulation in Mendelian diseases.
  54. RBM protein family: Focusing on the occurrence, progression and treatment of cancer.
  55. 1H, 13C, and 15N resonance assignments and solution structure of the first double-stranded RNA-binding domain of DExH-Box Helicase 30 (DHX30).
  56. A nuclear role for the contractile protein troponin I/UNC-27 in regulating muscle aging in C. elegans.
  57. Second-Generation Acyl Modifications Stabilize RNA, Support Translation, and Suppress Cytokine Responses.
  58. Tyrosine nitration: An emerging mechanistic landscape in neurodegeneration and cardiopulmonary disease.
  59. Mechanistic insights into RAN translation within the Huntingtin coding sequence.
  60. Mitochondrial dysfunction of renal tubular epithelial cells in chronic kidney disease-associated fibrosis: from organelle homeostasis to multicellular remodeling.
  61. Chemoreceptor complexes signal through a protein-ordering and stabilization mechanism.
  62. Glutamine metabolism in health and disease.
  63. A Quantitative Two-Channel Genetic Reporter for Selenocysteine Biosynthesis and Incorporation.
  1. Clin Interv Aging. 2026 ;21 626483
    Dysregulated mRNA Translation in Alzheimer's Disease: Mechanisms, Therapeutic Opportunities, and Challenges for Clinical Translation.
    Ling Li, Fangyu Dai, Haipeng Liu, Songbin He, Xiong Zhang, Qing-Qing Tao.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder and a growing public health concern. Its core pathological features include cerebral amyloid-β deposition and tau aggregation. mRNA translation is a tightly regulated process essential for gene expression and protein synthesis. It plays critical roles in neural development, synaptogenesis, and synaptic plasticity. In recent years, dysregulated translational control has been recognized as an important pathogenic mechanism in several neurological diseases, including AD. This review provides an integrated overview of the biological basis and mechanisms of dysregulated mRNA translation in AD, including translation initiation and elongation, local synaptic translation, abnormalities in RNA-binding proteins and stress granules, tRNA dysregulation, and the effects of AD-related genetic factors on translational control. Beyond the classic mechanisms of protein aggregation, the onset and progression of AD are also accompanied by abnormal translational regulation, involving initiation, elongation, and local synaptic translation. A major feature of these abnormalities is the coexistence of suppressed global protein synthesis and selectively enhanced translation of certain disease-related mRNAs, involving the integrated stress response, eIF2α/eIF4E signaling, eEF2K/eEF2 pathway, and RNA-binding protein dysfunction. Translational dysregulation provides a new perspective for understanding the molecular pathology of AD and has prompted the exploration of interventions targeting key nodes in translational control. Strategies targeting the integrated stress response, cap-dependent translation initiation, eEF2K, and tau-RNA-binding protein interactions have shown potential to improve synaptic function and cognitive phenotypes in animal models, although their safety and clinical translatability require further evaluation. This review provides an up-to-date reference for understanding translation-centered mechanisms in AD and evaluating emerging therapeutic strategies targeting translational control.
    Keywords:  RNA-binding proteins; alzheimer’s disease; mRNA translation; translational dysregulation
    DOI:  https://doi.org/10.2147/CIA.S626483
  2. Cancer Gene Ther. 2026 Oct 07.
    RSL24D1 links ribosome biogenesis to p53 activation in melanoma.
    Leonie Stahl, Sebastian Staebler, Anja K Bosserhoff.
      Melanoma cells exhibit elevated translation activity and rely on intact ribosomes to sustain their high protein synthesis demand. To support this process, efficient ribosome biogenesis is essential. RSL24D1 is a ribosome biogenesis factor required for late-stage maturation of the 60S ribosomal subunit. By ensuring correct ribosomal assembly, RSL24D1 supports global protein translation and maintains cellular homeostasis. Transcript and protein analyses revealed that RSL24D1 is upregulated in melanoma cells compared to normal human epidermal melanocytes. This overexpression correlates with reduced patient survival, suggesting an oncogenic role. Reduction of RSL24D1 expression impaired protein synthesis, decreased cell growth and resulted in the accumulation of unincorporated ribosomal proteins RPL5 and RPL11, which form the 5S RNP complex and inhibit the binding of MDM2 to p53. This inhibition stabilised p53 and activated downstream targets, including CDKN1A, resulting in G1 phase arrest and a senescence-like phenotype. These findings identify RSL24D1 as a critical component linking ribosome biogenesis to the p53 stress response. Targeting RSL24D1 creates a translational bottleneck, suppressing cell growth in p53 wild-type and p53-mutant cancer cells, highlighting it as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41417-026-01089-6
  3. Mol Cell. 2026 Oct 07. pii: S1097-2765(26)00629-5. [Epub ahead of print]
    Ribosome remodeling drives translation adaptation during viral infection and cellular stress.
    Hsin-Yu Tsai, Luochen Liu, Rebecca H Fleming, Julian Mintseris, Derrick Ekanayake, Jing A Guo, Xin Gu, Steven P Gygi, Amy S Y Lee.
      The ribosome is the highly conserved molecular machine that decodes mRNAs during protein synthesis. Here, we discover that, while traditionally thought to consist of a uniform set of proteins, ribosome composition is reprogrammed to adapt to intrinsic and external cellular perturbations. During infection of human cells by non-segmented negative-sense viruses, viral entry into cells recruits the large ribosomal subunit protein rpL40 to a non-canonical site on the small subunit of 80S ribosomes near the mRNA entry site. These specialized ribosomes preferentially bind viral mRNAs to drive enhanced viral protein synthesis that is critical for replication under host pressures. Unexpectedly, we find that viruses have co-opted this translation pathway from a previously unrecognized endogenous ribosome remodeling program in which metabolic stress alters ribosome structure to promote mRNA translation required for cell survival. Thus, ribosome remodeling is a conserved mechanism that enables dynamic protein synthesis across pathogen and cellular adaptation.
    Keywords:  cell stress; ribosome; ribosome heterogeneity; rpL40; translation regulation; virus
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.008
  4. Mol Cell. 2026 Oct 09. pii: S1097-2765(26)00664-7. [Epub ahead of print]
    Oligo(uridine) tailing and exonucleolytic decay drive 40S ribosome degradation in response to stress.
    Frances F Diehl, Allen R Buskirk, Rachel Green.
      Stresses like starvation trigger degradation of mature 40S ribosomes, requiring the coordinated breakdown of large, stable RNA-protein complexes. The atypical kinase RIOK3 orchestrates degradation by binding ubiquitylated 40S ribosomes and promoting rRNA decay. However, the mechanisms and factors that mediate rRNA decay remain unknown. Here we find that in response to starvation, RIOK3 recruits the terminal uridylyl-transferase TUT7 and the exonuclease DIS3L2 to 40S ribosomes. Sequencing analyses show that TUT7 adds oligo(uridine) tails to the 3' end of 18S rRNA in these ribosomes. DIS3L2 subsequently recognizes uridylated 18S rRNA and carries out 3'-5' decay. We identify major decay intermediates that undergo further uridylation in a process of iterative uridylation and decay. Loss of DIS3L2 impairs 18S rRNA decay during starvation and leads to accumulation of uridylated 18S rRNA. Together these findings define a mechanism for ribosome degradation in human cells in which oligo(uridine) tailing drives decay of rRNA from ribosomes.
    Keywords:  DIS3L2; RIOK3; RNA decay; Ribosome; TUT7; rRNA; starvation; stress response; uridylation
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.021
  5. bioRxiv. 2026 Sep 02. pii: 2026.09.01.748722. [Epub ahead of print]
    Temozolomide Induces Aberrant RNA Alkylation and Widespread Translational Repression.
    Jayden Rhodes, Abigail Grace Johnston, Katherine Marlow Brazell, Xisheng Liu, John L Hartman, Zhangli Su.
      Temozolomide (TMZ) is a frontline alkylating chemotherapy, yet its direct impact on RNA modification and global translation dynamics remains poorly understood. Here, we demonstrate that TMZ induces pervasive RNA alkylation causing severe translational impairment. TMZ directly deposits aberrant methyl groups onto single-stranded mRNA in vitro , creating physical lesions that lower translational efficiency. In glioblastoma cells, acute TMZ exposure triggers a rapid, widespread accumulation of m 7 G on cellular RNAs, leading to the significant attenuation of global protein synthesis. Nanopore direct RNA sequencing identified distinct guanine-specific error signatures and sequence context preferences associated with TMZ-induced damage. Using a quantitative yeast spike-in ribosome profiling strategy, we mapped this translational repression at transcript-level, revealing a global downregulation of translational efficiency. This widespread repression disproportionately targets highly interconnected networks essential for cellular proliferation, specifically chromosome organization. We show that the severity of this translational repression is driven by a transcript's coding guanine density, stability and translation initiation speed. Together, our findings suggest that TMZ-induced alkylation targets stable, highly translated, guanine-rich transcripts. This establishes aberrant RNA methylation and subsequent translational arrest as a potential mechanism of temozolomide cytotoxicity.
    DOI:  https://doi.org/10.64898/2026.09.01.748722
  6. Plant Signal Behav. 2026 12 31. 21(1): 2744693
    Protein homeostasis and inter-organellar signaling under salt stress.
    Susmita Das, Yamshi Arif, Hesam Mousavi, Henrik Aronsson, Nadia Bazihizina, Mohammad Sarraf.
      Salinity is a major abiotic constraint on plant growth, productivity, and global food security. It disrupts cellular protein homeostasis (proteostasis) at every step, from synthesis to degradation. Plant survival under salt stress therefore depends on the coordinated regulation of protein synthesis, folding, post-translational modification, trafficking, quality control, and turnover. The individual contributions of the nucleus, ribosomes, endoplasmic reticulum (ER), and Golgi apparatus to salinity responses are increasingly well described, but how these compartments communicate remains far less understood. This review synthesizes current evidence on this inter-organellar signaling network, addressing four questions: how salinity-induced osmotic, ionic, and oxidative stress reprograms nuclear transcription and chromatin state; how ribosomes sustain selective translation of protective proteins while clearing stalled or damaged translational products; how the ER expands its folding capacity through the unfolded protein response and removes terminally misfolded proteins by ER-associated degradation; and how the Golgi sustains glycosylation, sorting, and secretion of the transporters needed for ion and osmotic homeostasis. Beyond these organelle-level responses, the review discusses two signaling layers that couple them into a single circuit: post-translational modifications (phosphorylation, ubiquitination, SUMOylation, and redox- and nitrosative/persulfidation-based marks) and phytohormone/gasotransmitter signals, including abscisic acid, nitric oxide, hydrogen sulfide, carbon monoxide, and melatonin. By framing proteostasis as an emergent property of nucleus-ribosome-ER-Golgi coordination rather than of any single compartment, this review identifies specific inter-organellar signaling nodes as candidate targets for breeding or engineering salinity-resilient crops.
    Keywords:  Salt stress; gasotransmitter signaling; inter-organellar signaling; post-translational modification; protein homeostasis; unfolded protein response
    DOI:  https://doi.org/10.1080/15592324.2026.2744693
  7. Bioessays. 2026 Oct;48(10): e70194
    The Partition Code: How RNA Modifications Set the Address of Transcripts Among Membraneless Compartments: Covalent RNA Marks Set a Measurable, Reversible Spatial Address Among Membraneless Compartments-A Variable to Perturb, Not Just Observe.
    Hidenori Tani.
      Where a transcript goes among a cell's membraneless compartments-stress granules, P-bodies, paraspeckles, nuclear speckles-is an addressable, rewritable property that this article proposes chemical modifications of RNA help write. The code's output depends on the transcript's role: for client messenger RNAs, an apparent partition coefficient (Kpart), its enrichment in a condensate; for the rare long noncoding RNAs acting as architectural scaffolds, the saturation concentration that decides whether the compartment forms at all. This client/scaffold asymmetry is the framework's central proposal, its scaffold arm as yet untested. Only m6A has cellular partitioning evidence; A-to-I editing sets nuclear address by a related route, and the remaining marks are candidates or structure-based predictions. The value is a variable and a falsifiable test: perturb a mark at fixed sequence and state, and ask whether the address moves. It reframes scattered epitranscriptomic and condensate biology as one control problem.
    Keywords:  A‐to‐I editing; N6‐methyladenosine (m6A); RNA localization; RNA modifications; biomolecular condensates; liquid–liquid phase separation; partition coefficient
    DOI:  https://doi.org/10.1002/bies.70194
  8. Cell Metab. 2026 Oct 06. pii: S1550-4131(26)00381-5. [Epub ahead of print]38(10): 1949-1951
    You are what you eat and translate: Feeding the code to fight cancer and viruses.
    Adrianna Dabrowska, Davide Ruggero.
      How nutrients shape gene expression has remained a fundamental question. Wu et al.1 show that extracellular arginine directly remodels the tRNA-codon axis, controlling codon-dependent translation of major histocompatibility complex class I mRNA independently of canonical amino acid stress signaling. This nutrient-sensing mechanism regulates immunity in colorectal cancer and viral infection while revealing new opportunities for therapeutic intervention.
    DOI:  https://doi.org/10.1016/j.cmet.2026.09.006
  9. Proc Natl Acad Sci U S A. 2026 Oct 13. 123(41): e2533263123
    Tyrosine phosphorylation unfolds nucleophosmin and disrupts its integration into the nucleolus.
    Rafael L Giner-Arroyo, Adrián Velázquez-Campoy, Miguel A De la Rosa, Irene Díaz-Moreno.
      Nucleophosmin (NPM1) is a multifunctional nucleolar protein essential for ribosome biogenesis, genome stability, and stress responses. Its integration into the nucleolus depends on its oligomerization and multivalent interactions that enable liquid-liquid phase separation (LLPS). Here, we investigate how tyrosine phosphorylation at Tyr17, Tyr29, and Tyr67 located within the interface between monomers at the N-terminal oligomerization domain regulates NPM1 structure and function. Replacing tyrosines with p-carboxymethyl-L-phenylalanine as phosphomimetic substitutions, we show that phosphorylation at Tyr17 and Tyr67 disrupts key intermonomer interactions and destabilizes the NPM1 pentameric assembly, which drives an order-to-disorder transition and impairs binding to nuclear partners. Consequently, dual phosphorylation at Tyr17 and Tyr67 disturbs both homotypic and heterotypic LLPS, thereby impairing incorporation of NPM1 into the nucleolus. This altered localization of NPM1 serves as a hallmark of p53 activation, driven both by nucleoplasmic NPM1 and by the release of ARF from NPM1-dependent sequestration in the nucleolus. Altogether, our results provide a molecular mechanistic explanation on how phosphorylation-induced structural and dynamic changes drive the release of NPM1 from the nucleolus under genotoxic stress.
    Keywords:  liquid-liquid phase separation; nucleolus; nucleophosmin; protein oligomerization; tyrosine phosphorylation
    DOI:  https://doi.org/10.1073/pnas.2533263123
  10. mBio. 2026 Oct 09. e0170526
    BR-bodies link RNA homeostasis to stress tolerance and intracellular fitness in Brucella.
    Kaveendya S Mallikaarachchi, Rosemary Northcote, Thomas Kim, Melene A Alakavuklar, Vincent A Lawal, Vidhyadhar Nandana, Aretha Fiebig, Jared M Schrader, Sean Crosson.
      Bacterial gene expression depends on the coordinated regulation of RNA synthesis, processing, and decay. The conserved RNA degradosome scaffold, ribonuclease E (RNase E), assembles into phase-separated bacterial ribonucleoprotein bodies (BR-bodies) through its C-terminal intrinsically disordered region (IDR). This IDR also scaffolds recruitment of degradosome client proteins that carry out post-transcriptional gene regulation. Whether BR-bodies regulate virulence programs to support infection, however, is largely undefined. We show that RNase E of the intracellular pathogen Brucella ovis forms RNA-dependent condensates in vivo and phase-separates with RNA in vitro, with the IDR necessary and sufficient for BR-body assembly. Deleting the IDR [rne(ΔIDR)] did not impair growth but sensitized Brucella to host-relevant oxidative and cell-envelope stressors. Transcriptome-wide profiling that simultaneously resolved mRNA decay and processing revealed that BR-bodies primarily accelerate mRNA turnover while stabilizing a distinct subset of transcripts. Notably, BR-bodies control the processing and levels of virB type IV secretion system mRNA and the turnover of its key activators, linking condensate-based RNA regulation to a core virulence pathway. Consistent with virB dysregulation, the rne(ΔIDR) mutant was severely attenuated in mammalian macrophages. To test whether phase separation is sufficient for BR-body function, we replaced the B. ovis IDR with the highly divergent Caulobacter crescentus IDR. This chimera assembled BR-bodies but rescued fitness incompletely, fully restoring oxidative-stress resistance but not cell-envelope stress resistance or intracellular fitness. BR-bodies therefore link RNA metabolism to Brucella stress resistance and infection, and their full function requires both phase separation and additional native IDR-specific activities, such as degradosome interactions.IMPORTANCEBiomolecular condensates are non-membrane-bound organelles that organize biological processes across all domains of life, but their role in bacterial infection is not well characterized. We show that Brucella, an intracellular bacterial pathogen and causative agent of the disease brucellosis, relies on biomolecular condensates called bacterial ribonucleoprotein bodies (BR-bodies) to control RNA stability and regulate gene expression. Without BR-bodies, Brucella is sensitized to host-relevant chemical stresses, cannot properly regulate essential infection machinery, and has severely diminished fitness within mammalian host cells. These results indicate that control of RNA levels by biomolecular condensates is required for Brucella survival within animal hosts, providing evidence that phase separation is a fundamental mechanism underlying Brucella adaptation to the hostile environment encountered during infection.
    Keywords:  BR-bodies; Brucella; RNase E; biomolecular condensates; mRNA decay; stress response; type IV secretion system
    DOI:  https://doi.org/10.1128/mbio.01705-26
  11. bioRxiv. 2026 Aug 13. pii: 2026.08.10.743958. [Epub ahead of print]
    Deletion of the gene for a cyanobacterial ribosome-associated protein affects the carbon/nitrogen metabolism.
    Nouha Abdelaziz, Alexander Kraus, Stefan Timm, Friedel Drepper, Viktoria Reimann, Marc Broghammer, Bettina Knapp, Antonio López-Lozano, Ravi Shankar Ojha, Bettina Siebers, Michael Y Galperin, José Manuel García-Fernández, Manuel Brenes-Alvarez, Pitter F Huesgen, Martin Hagemann, Wolfgang R Hess.
      In contrast to their important structural and regulatory functions, such as in the metabolism of cyanobacteria, genes encoding small proteins are often not well characterized. Cyanobacteria use redox equivalents and energy from oxygenic photosynthesis to produce organic carbon compounds from inorganic carbon (C i ) and organic nitrogen compounds from inorganic nitrogen sources. Therefore, the assimilation and metabolism of carbon and nitrogen are coordinated at multiple levels in cyanobacteria. Here, we analyzed the Synechocystis sp. PCC 6803 gene ssr3189 encoding a 55 amino acids protein. Orthologs were detected in 665 cyanobacterial genomes defining COG5794 in the Database of Clusters of Orthologous Genes. Homologs in several eukaryotic algae suggest that Ssr3189 is an important protein that originated in cyanobacteria, was retained in algae after endosymbiosis, but was lost in plants. Polynucleotide kinase assays validated Ssr3189 as an RNA-binding protein. Deletion of ssr3189 resulted in lower pigmentation, delayed growth, and alterations in the expression of genes encoding transporters for nitrogen and C i , and metabolic enzymes. Metabolomic analysis revealed a substantial overaccumulation of glutamine and tricarboxylic acid cycle intermediates in the deletion mutant, and further differences in the amino acid and organic acid pools compared to the wild type. Co-immunoprecipitation analysis yielded ribosomal protein S21, enolase and the Cas6-1 endoribonuclease as the most strongly co-enriched proteins, together with all other ribosomal proteins and a small set of metabolic enzymes. These findings are consistent with observations that ssr3189 encodes the ribosome-associated protein cS24 and suggest that it connects translation with metabolic control, and, potentially, RNA decay.
    IMPACT STATEMENT: Despite considerable progress in analyzing microbial genomes, there are still substantial numbers of uncharacterized gene functions. Here, we analyzed a mutant lacking gene ssr3189 that is widely conserved, but phenotypically uncharacterized in cyanobacteria. This gene is important for growth at the optimum temperature and essential at lower temperatures. In its absence, important metabolites were overaccumulated, while genes involved in nitrogen and C i uptake were dysregulated. The encoded protein binds RNA and interacts with proteins involved in translation and metabolism. The findings are consistent with a function as a ribosomal protein bridging protein synthesis and the regulation of metabolism.
    DOI:  https://doi.org/10.64898/2026.08.10.743958
  12. Ageing Res Rev. 2026 Oct 08. pii: S1568-1637(26)00392-2. [Epub ahead of print] 103400
    Protein damage and repair in aging: mechanisms, homeostasis and disease.
    Alex Lyakhovich, Luigi Ferrucci.
      Proteome integrity is continuously challenged by diverse forms of molecular damage, yet, in contrast to DNA, proteins have long been considered largely disposable rather than repairable. This view has shaped the prevailing paradigm of proteostasis, in which damaged proteins are primarily eliminated and replaced. However, emerging evidence from both prokaryotic and eukaryotic systems indicates that enzymatic protein repair is more widespread and functionally significant than previously appreciated. In this review, we re-examine protein repair as a distinct and under-recognized component of proteostasis, complementing degradation and resynthesis pathways. We provide a mechanistic framework that integrates major forms of protein damage, including oxidation, nitration, chlorination, glycation, and spontaneous isomerization, with their corresponding repair systems. We argue that the apparent scarcity of protein repair pathways reflects not their absence, but the biochemical complexity, energetic cost, and substrate heterogeneity inherent to protein damage. Importantly, we connect these mechanisms to the pathogenesis of major age-related diseases, including neurodegenerative, cardiovascular, metabolic disorders, and cancer, highlighting how the progressive failure of protein repair contributes to proteome instability and cellular dysfunction. We further discuss the energetic trade-offs between repair and turnover, proposing that repair is selectively deployed under conditions where replacement is inefficient or deleterious. By integrating biochemical, evolutionary, and translational perspectives, this review positions protein repair as an axis of proteostasis and outlines emerging opportunities for therapeutic intervention targeting protein damage in agingaging and disease.
    Keywords:  Protein repair; cancer; cardiovascular; metabolic disorders; neurodegeneration; protein damage
    DOI:  https://doi.org/10.1016/j.arr.2026.103400
  13. J Neurochem. 2026 Oct;170(10): e70565
    Synaptic Proteostasis in Health and Disease.
    Paul G Donlin-Asp, Emma L Clayton.
      Neurons rely on tightly coordinated mechanisms of protein synthesis and degradation to maintain cellular homeostasis, a process known as proteostasis. Given their highly polarised and compartmentalised nature, regulation of proteostasis is especially important at neuronal synapses, which are spatially distant from the soma yet require rapid on-demand adaptation of the synaptic proteome. Neurons meet their demand for synaptic proteostasis through localised mRNA transport and translation, alongside specialised pathways for protein degradation. Recent advances reveal that thousands of transcripts localise to distal neuronal compartments and that their distribution may be shaped by RNA stability, RNA dynamics, and organelle-hitchhiking transport mechanisms. In parallel, processes such as synaptic autophagy and endolysosomal trafficking are crucial for maintaining synaptic structure and neurotransmission. Disruptions in these finely balanced mechanisms are a common underlying feature of various neurological disorders, including fragile X syndrome, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. This overview highlights key milestones and remaining questions in synaptic proteostasis, focusing on how local protein synthesis and degradation work together to preserve synaptic integrity and how their dysregulation can lead to disease.
    Keywords:  autophagy; local translation; neurodegenerative disease; neurodevelopmental disease; proteostasis; synapse
    DOI:  https://doi.org/10.1111/jnc.70565
  14. bioRxiv. 2026 Aug 10. pii: 2026.08.07.743554. [Epub ahead of print]
    NET1 mRNA localization to the midbody is required for Arp2/3-dependent initiation of mitotic abscission.
    Katherine F Vaeth, Andrew J Neumann, Frances Zorensky, Xinrui Wei, Rytis Prekeris, J Matthew Taliaferro.
      The recruitment and activation of abscission machinery following mitosis is tightly spatiotemporally regulated, yet the mechanisms underlying this remain poorly understood. We find that RNA localization and local translation at the midbody governs when and where abscission-regulating proteins are expressed. The 3' UTR of NET1 mRNA contains an element that is necessary and sufficient for RNA targeting to the midbody. Mislocalization of NET1 mRNA results in a loss of NET1 protein, a Rho family GEF, throughout the intercellular bridge, delaying abscission and slowing cell proliferation. Arp2/3-mediated branched actin accumulation at the midbody, which is necessary for abscission, requires localized NET1 protein that is competent for binding Rho family GTPases. These findings establish midbody RNA localization and local translation as a key regulatory layer over abscission timing and identify a role for NET1 as a regulator of Arp2/3-mediated branched actin accumulation at the abscission site.
    DOI:  https://doi.org/10.64898/2026.08.07.743554
  15. Proc Natl Acad Sci U S A. 2026 Oct 13. 123(41): e2614934123
    Pyrrolysine supply and demand shapes the translational landscape in Methanosarcina acetivorans.
    Grace D Britt, Daniel R Utter, Yeonsoo Park, Victoria J Orphan, Rodney Tollerson.
      The amber stop codon (UAG) can encode for pyrrolysine (Pyl) or be read as a stop codon by methylamine-metabolizing organisms including methanogenic archaea. The fate of UAG is decided during the decoding step of translation by competition between the pyrrolysine-aminoacylated transfer RNA (Pyl-tRNAPyl) and release factor. To further understand the consequences of pyrrolysine based genetic code expansion, we integrated RNA sequencing, tRNA charging analysis, and codon-resolved mono- and disome ribosome profiling in Methanosarcina acetivorans. During conditions of high pyrrolysine demand, we observed increased expression of the pyrrolysine biosynthetic operon with a concurrent increase in acylation of tRNAPyl and ribosome occupancy at UAG codons. During low pyrrolysine demand, the population of Pyl-tRNAPyl decreases and we observe a strong ribosome pausing signal during UAG decoding. We find that the dwell time on UAG codons is shorter during high demand, but ribosome collisions increase due to greater ribosome density on UAG-containing transcripts. Together, these results show how pyrrolysine demand modulates tRNA charging and controls elongation dynamics, clarifying the cellular consequences of decoding an ambiguous stop codon.
    Keywords:  Methanosarcina acetivorans; genetic code expansion; pyrrolysine; ribosome pausing; tRNA charging
    DOI:  https://doi.org/10.1073/pnas.2614934123
  16. Sci Adv. 2026 Oct 09. 12(41): eaeb6883
    Real-time single-molecule imaging in zebrafish embryos uncovers noncanonical translation.
    Maëlle Bellec, Jie Liang, Kenny Mattonet, Tatsuya Morisaki, Margaux Lay, Hans-Martin Maischein, Damien Avinens, Vincent Martinet, Delphine Muriaux, Timothy J Stasevich, Jérémy Dufourt, Didier Y R Stainier.
      Precise spatiotemporal control of protein synthesis is essential during embryogenesis, yet directly measuring translation kinetics in vivo remains challenging in vertebrates. In particular, it remains unclear how translation efficiency is determined for key developmental regulators and which kinetic steps limit their production. Here, we used ALFA array-based nascent chain labeling combined with lattice light-sheet microscopy to visualize bmp2b translation in real time and at single-molecule resolution in early zebrafish embryos. When combined with MS2/MCP labeling to visualize all bmp2b messenger RNA (mRNAs), we found that only some of them are being actively translated, suggesting that limited mRNA translation competence contributes to overall translation efficiency. We found that bmp2b translation operates below a maximal initiation regime, as replacement of its untranslated regions (UTRs) with viral UTRs increases ribosome loading. Furthermore, the bmp2b, but not actb2, 5'UTR supports cap-independent translation with ribosome loading comparable to cap-dependent initiation. Together, this approach provides a quantitative in vivo framework to dissect translation kinetics during early vertebrate development.
    DOI:  https://doi.org/10.1126/sciadv.aeb6883
  17. Biomark Res. 2026 Oct 09. pii: 134. [Epub ahead of print]14(1):
    RNA N4-acetylcytidine modification in health and cancer: molecular mechanisms, cellular plasticity, and therapeutic opportunities.
    Xiao-Yan He, Kang Du, Chaofu Yue, Chongxin Li, Yunze Zhu, Yuan Tang, Hanmin Wang, Mei Yang, Fei He, Xiulin Jiang.
      N⁴-acetylcytidine (ac⁴C) is an evolutionarily conserved RNA modification that was initially identified in transfer RNA (tRNA) and ribosomal RNA (rRNA). Increasing evidence has subsequently expanded its functional landscape to messenger RNA (mRNA) and multiple classes of non-coding RNAs (ncRNAs). As the best-characterized ac⁴C writer in mammals, N-acetyltransferase 10 (NAT10) orchestrates RNA structure, stability, processing, and translation, thereby governing fundamental physiological processes, including ribosome biogenesis, translational fidelity, proteostasis, cell fate determination, hematopoiesis, reproduction, and embryonic development. Cancer cells exploit the NAT10-ac⁴C axis to selectively stabilize or enhance the translation of oncogenic transcripts, reprogram tRNA and rRNA-dependent translational programs, and cooperate with non-canonical NAT10 functions, including R-loop regulation, protein acetylation, and RNA binding, to sustain uncontrolled proliferation, cancer stemness, metabolic reprogramming, DNA damage repair, invasion and metastasis, resistance to regulated cell death, and immune evasion. Consequently, the NAT10-ac⁴C axis has emerged as a central molecular hub linking RNA fate, the translational machinery, and adaptive tumor reprogramming. Therefore, phenotypes resulting from NAT10 depletion or pharmacological inhibition should not be indiscriminately attributed to reduced ac⁴C deposition in the absence of catalytic rescue experiments and site-specific validation. In this Review, we comprehensively summarize the molecular basis of ac⁴C, its substrate landscape, catalytic mechanisms, and determinants of substrate selectivity, as well as its physiological functions in normal tissues and pathological roles in cancer. We further compare the shared and context-dependent mechanisms by which the NAT10-ac⁴C axis drives malignant progression and therapeutic resistance across diverse cancer types. In addition, we critically evaluate current ac⁴C detection technologies, the hierarchy of substrate evidence, NAT10 inhibitors, targeted protein degradation strategies, rational combination therapies, biomarker-guided patient stratification, and therapeutic windows. Finally, we propose that future research should move beyond broad NAT10 inhibition toward identifying tumor-specific NAT10 dependencies and selectively disrupting oncogenic NAT10-RNA regulatory circuits through high-confidence ac⁴C atlases, site-specific RNA editing technologies, and precision delivery strategies.
    Keywords:  DNA damage repair; Epitranscriptomics; NAT10; N⁴-acetylcytidine; Precision oncology; RNA modification; RNA stability; Therapeutic resistance; Translational regulation; Tumor immunity; Tumor metabolism; ac⁴C
    DOI:  https://doi.org/10.1186/s40364-026-01014-x
  18. J Physiol Biochem. 2026 Oct 07. pii: 102. [Epub ahead of print]82(1):
    Emerging mechanisms of ATG8-independent non-canonical autophagy.
    Suvam Saha, Debasish Kumar Ghosh.
      ATG8-independent autophagy represents an emerging field of cellular degradation that challenges the long-held view that LC3/GABARAP lipidation is universally required for autophagosome formation and autophagic flux. Over the past decade, studies across mammals, plants, and protozoa have revealed that cells can execute degradative mechanisms through alternative macroautophagy, microautophagy-like pathways, and autophagy-like systems that operate with reduced or absent reliance on ATG8 proteins. These discoveries have reshaped the conceptual framework of autophagy by separating membrane biogenesis, cargo sequestration, and lysosomal delivery into potentially ATG8-uncoupled modules. ATG8-independent pathways are now recognized as important for stress adaptation, organelle quality control, developmental remodeling, and selective cargo degradation. This review summarizes the historical development, mechanistic diversity, and biological relevance of ATG8-independent autophagy, and discusses its implications for disease biology and therapeutic targeting. Understanding these unconventional pathways will be essential for a complete view of autophagic regulation in health and disease.
    Keywords:  ATG8-independent autophagy; Autophagy machinery diversity; Autophagy regulation; Non-canonical autophagy; Organelle quality control; Stress-induced cellular degradation
    DOI:  https://doi.org/10.1007/s13105-026-01243-6
  19. Front Mol Neurosci. 2026 ;19 1964213
    Expression and role of HSPA5 in environmental toxin-induced neurological disorders.
    Yurong Wang, Yang Lv, Ruidong Zhao, Xin Guo, Jing Gao, Tong Wang, Dongmei Yao, Xin Li, Bingchun Liu, Jianlong Yuan.
      HSPA5 is a member of the HSP70 family of heat shock proteins (HSPs) and functions as a chaperone protein within the endoplasmic reticulum (ER). It plays a role in maintaining ER homeostasis, assists in correct protein folding, and triggers the unfolded protein response. Environmental toxins-such as heavy metals, microplastics (MPs), and air pollutants-can cause cellular damage. These toxins can trigger ER stress, resulting in the buildup of proteins that are misfolded or not properly folded, which in turn upregulates HSPA5 expression. Moderate activation of HSPA5 serves as a protective mechanism aimed at restoring protein homeostasis and promoting cell survival; however, sustained and severe ER stress may cause HSPA5 to malfunction, ultimately leading to the activation of the apoptotic pathway and resulting in cell death. Furthermore, HSPA5-mediated mechanisms are closely associated with the prodromal initiation and subsequent escalation of neurodegenerative syndromes. This article focuses on the role of HSPA5 in environmental toxin-induced neurotoxicity and neurodegenerative diseases, with the aim of investigating changes in HSPA5 expression and its regulatory functions in neurotoxicity, thereby providing new strategies for the study of environment-related neurodegenerative diseases.
    Keywords:  ER stress; HSPA5; cellular damage; environmental toxins; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fnmol.2026.1964213
  20. Med Oncol. 2026 Oct 08. pii: 316. [Epub ahead of print]43(11):
    YTHDF2 drives malignant progression in cutaneous melanoma through m⁶A-dependent HMOX1-mediated ferroptosis.
    Da Gu, Yulin Sun, Jinpeng Sun, Weiting Kang, Huanmin Lou, Xiaojing Li.
      N6-methyladenosine (m6A) modification plays a critical role in eukaryotic mRNA and is significantly associated with cutaneous melanoma. This study investigated the role of the m6A-binding protein YTHDF2 in the pathogenesis of cutaneous melanoma and its potential therapeutic applications. Analyses of public databases indicated that YTHDF2 exhibited elevated expression in various cancers, including cutaneous melanoma, where its levels positively correlated with PD-L1 and negatively correlated with immune and stromal scores. Functionally, the downregulation of YTHDF2 in melanoma cells suppressed proliferation and increased the population of Annexin V/PI--positive cells, an effect that was rescued by the ferroptosis inhibitor, highlighting YTHDF2's involvement in ferroptosis regulation. YTHDF2 knockdown resulted in increased intracellular Fe2+ levels, malondialdehyde, reactive oxygen species, and lipid peroxidation, alongside a reduction in glutathione-effects that were reversed upon ferroptosis inhibition. In vivo studies corroborated the regulatory role of YTHDF2 in ferroptosis. Mechanistically, integrated RNA-seq and RIP-seq analyses demonstrated that YTHDF2 could bind to m6A on HMOX1 transcripts, destabilizing its mRNA and thus regulating HMOX1 expression. Moreover, metformin was shown to inhibit YTHDF2 expression, promoting ferroptosis in melanoma cells. In summary, YTHDF2 modulates ferroptosis in melanoma through the regulation of m6A-dependent HMOX1 mRNA stability, suggesting it as a promising therapeutic target. The capacity of metformin to suppress YTHDF2 indicates its potential utility in hindering melanoma progression.
    Keywords:  Cutaneous Melanoma; Ferroptosis; HMOX1; M6A; YTHDF2
    DOI:  https://doi.org/10.1007/s12032-026-03427-y
  21. bioRxiv. 2026 Aug 11. pii: 2026.08.10.744006. [Epub ahead of print]
    Rescue of ribosomal protein bL27 in Streptococcus pneumoniae TIGR4 by an alternate protease.
    Amarshi Mukherjee, Mohamed O Nasef, Patrick M Lindstrom, Nehaal Akavaram, Vipin Chembilikandy, Eriel Martinez, Carlos J Orihuela, Terje Dokland.
      Streptococcus pneumoniae is a major human respiratory pathogen. The bacterial 70S ribosome is a target of many clinically important antibiotics. The N-terminus of ribosomal protein bL27 extends into the peptidyl transferase center and contributes to the translation process. In Firmicutes, full length bL27 contains an 8-12 amino acid N-terminal extension that is absent from Gram-negative bacteria. This extension is cleaved by the protease Prp, which is absent from organisms lacking the extension. Prp-mediated cleavage of bL27 is essential in Staphylococcus aureus , and Prp has been proposed as a potential antibiotic target. Here, we show that in S. pneumoniae strain TIGR4, a Δ prp mutant remained viable, and produced ribosomes containing cleaved bL27, whereas deletion of prp was not tolerated in strain D39. These results suggested the presence of an alternate bL27-processing protease in TIGR4 that was absent from D39. Using a combination of genomics, proteomics and biochemical analyses, we identified this enzyme as the product of previously uncharacterized gene SP_1145 , encoding a protease that we named Ribosome rescue protease (Rrp). SP_1145 is carried on a mobile genetic element that is present in strain TIGR4, but absent from D39. Our findings shed light on an alternative mechanism for bL27 maturation, and indicate that some strains of S. pneumoniae harbor horizontally acquired redundant pathways for this essential ribosome processing step.
    DOI:  https://doi.org/10.64898/2026.08.10.744006
  22. J Med Microbiol. 2026 Oct;75(10):
    Disruption of dnaK results in transcriptional reprogramming of biofilm-associated pathways in Clostridioides difficile.
    Megan G Taggart, Carla S Möller-Levet, William J Snelling, Patrick J Naughton, Roberto M La Ragione, Barry M G O'Hagan, James S G Dooley, Nigel G Ternan.
      Introduction.Clostridioides difficile is an opportunistic enteric pathogen posing significant challenges in human and animal healthcare due to the recurrent nature of infections and associated financial burden. The molecular chaperone protein, DnaK (Hsp70), encoded by dnaK, plays a central role in the heat stress response and protein homeostasis. Disruption of dnaK in C. difficile 630Δerm has previously been associated with increased biofilm formation and multiple phenotypic alterations.Gap Statement. Although disruption of dnaK has been shown to alter biofilm formation and multiple phenotypes in C. difficile, the global transcriptional mechanisms linking DnaK to biofilm development and stress adaptation remain poorly understood.Aim. This study aimed to characterize the global transcriptional response associated with dnaK disruption during planktonic and biofilm growth to identify pathways linking the DnaK-mediated stress response with biofilm formation.Methods. This study investigated the global transcriptional changes associated with dnaK disruption during planktonic and colony biofilm culture. Colony biofilms of C. difficile strains 630, 630Δerm and 630Δerm:dnaK were cultured on mixed nitrocellulose ester semi-permeable membranes and examined structurally using low-vacuum scanning electron microscopy. Total RNA was extracted from both planktonic cultures and 24 h colony biofilms, followed by Illumina RNA sequencing. Differential gene expression analysis was performed using DESeq (P adj<0.05). Gene set enrichment analysis (Kyoto Encyclopedia of Genes and Genomes [KEGG] and Gene Ontology) was conducted to identify significantly enriched metabolic pathways and biological processes.Results. Disruption of dnaK resulted in global transcriptomic remodelling, particularly during biofilm culture, where 72.4% of genes were significantly differentially expressed relative to planktonic culture. A core number of pathways were involved in biofilm formation in all strains, including increased sporulation with reduced translation, amino acid biosynthesis and flagellar assembly. The dnaK mutant exhibited a unique pattern of enrichment of pathways associated with cell division, peptidoglycan synthesis, carbon metabolism and amino acid biosynthesis, alongside a coordinated reduction of motility and chemotaxis pathways.Conclusion. Disruption of the dnaK gene appears to link the stress response to biofilm formation through a number of pathways associated with biofilm development. Understanding this link may identify systems relevant to persistent and recurrent infections.
    Keywords:  Clostridioides difficile; biofilm; dnaK; stress response
    DOI:  https://doi.org/10.1099/jmm.0.002212
  23. Life Sci Alliance. 2026 Dec;pii: e202603847. [Epub ahead of print]9(12):
    Allele-resolved monosome and polysome sequencing identifies cis-variants affecting mRNA translation.
    Laura Alunno, Ilaria Massignani, Meriem Hadjer Hamadou, Fabio Mazza, Daniele Peroni, Romina Belli, Erik Dassi, Alessandro Romanel, Alberto Inga.
      To prioritize germline genetic variants affecting mRNA fate at the translational level, we used sucrose gradient-based isolation of 80S monosomes and polysomes, followed by RNA sequencing in RPE-1 cells, under mock and nutlin treatment conditions. Differential gene expression analysis confirmed a canonical p53 response. Heterozygous SNPs and SNVs were identified from the RNA-sequencing data, and allelic fractions were calculated for total, monosomal, and polysomal mRNAs. Variants showing reproducible allelic fraction differences across fractions beyond experimental variability were defined as tranSNPs. Among over 7,000 heterozygous variants analyzable in polysomal RNA and over 5,000 in mRNAs associated with monosome-enriched fractions, 1,247 in 1,015 genes displayed a significant imbalance. Reporter assays performed in RPE-1 and HCT116 cells validated allelic or haplotype effects for 17 selected variants in UTRs and coding regions, confirming differences in 15 cases, with evidence of cell line-specific responses. Proteomic analysis supported allelic imbalance for a few selected missense variants. Monosome-enriched fractions improved sensitivity in measuring allelic imbalances without introducing a tranSNP positional bias, suggesting that 80S profiling enhances detection of allele-specific translational regulation in RPE-1 cells.
    DOI:  https://doi.org/10.26508/lsa.202603847
  24. J Neurochem. 2026 Oct;170(10): e70562
    Dual Roles of p53-Related Protein Kinase in Cytoskeletal Remodeling and Translational Control.
    Emiliano Molina, David Villarroel-Campos, Manuel Muñoz, Álvaro Glavic, Christian Gonzalez-Billault.
      P53-related protein kinase (PRPK; TP53RK) is an evolutionarily conserved atypical kinase whose biology reveals an unexpected integration of translational control, cytoskeletal regulation, and cell-type-specific stress responses. As a core component of the TCTC complex (Threonyl-Carbamoyl Transferase Complex), PRPK participates in the universally conserved synthesis of the tRNA modification t6A, an essential process for translational fidelity, proteostasis, and cellular viability. Structural and biochemical studies from yeast to humans highlight a deeply conserved ATPase-driven mechanism in which PRPK undergoes conformational rearrangements to activate the catalytic subunit Tcs3, thereby coordinating tRNA positioning. Beyond this canonical role, PRPK displays additional functions. In Drosophila and mammalian systems, PRPK engages cytoskeletal regulators, including Rab35 and Arp2/3 subunits, to influence actin organization, neuronal polarity, and cell migration. These interactions suggest a second, TCTC-independent functional module through which PRPK integrates signaling pathways such as AKT and TOPK to shape cell survival, axon specification, and tumor progression. Dysregulation of PRPK in human disease further underscores its pleiotropy, as gain-of-function mechanisms promote oncogenesis and metastasis. In contrast, loss-of-function mutations in PRPK or other TCTC components cause Galloway-Mowat syndrome, characterized by microcephaly, nephrotic syndrome, and profound defects in proteostasis and cytoskeletal integrity. This Perspective synthesizes emerging concepts of PRPK as a dual-role regulator, acting in tRNA biology as well as in cytoskeletal and stress responses. We delineate unresolved questions regarding substrate identity, structural regulation, cell-type specificity, and the feasibility of selectively targeting PRPK for therapeutic purposes. Taken together, these findings reveal the richness and complexity of PRPK functions as a molecular regulator of translation, signaling, and cytoskeletal dynamics that are evolutionarily and mechanistically intertwined.
    DOI:  https://doi.org/10.1111/jnc.70562
  25. Nucleic Acids Res. 2026 Sep 22. pii: gkag918. [Epub ahead of print]54(18):
    Functional roles for viral RNA ribosylation in mammalian cells.
    John D Sears, Che-Kang Chang, Takayoshi Shirasaki, Paul Sylvester, Rebekah Dickmander, Nicholas A Saba, Wes Sanders, Mark T Heise, Nathaniel J Moorman.
      In mammalian cells, the addition of ADP-ribose to proteins and DNA plays well established roles in regulating cell function. Recently, RNA ribosylation was also found in mammalian cells under conditions of cell stress, though the functional consequences remain unclear. Here we find that infection with chikungunya virus, a positive strand RNA virus that causes frequent widespread epidemics, increases overall levels of RNA ribosylation in human fibroblasts. During infection, viral RNA is ribosylated by the PARP12 ribosyltransferase, which is counteracted by the viral nsP3 ribosylhydrolase. Increased viral RNA ribosylation resulted in decreased translation in cell-free systems and infected fibroblasts, and more rapid viral RNA decay. Further, ribosylated RNA potently induced the expression of antiviral host response genes. Together these data show the first functional consequences of RNA ribosylation in mammalian cells by showing that RNA ribosylation inhibits translation, decreases RNA stability, and creates a novel pathogen-associated molecular pattern that activates the host innate immune response. As macrodomains are present in multiple unrelated viruses, our data suggest RNA ribosylation is a novel component of cellular antiviral sensing pathway. These results define a framework for understanding how RNA ribosylation regulates RNA metabolism during viral infection.
    DOI:  https://doi.org/10.1093/nar/gkag918
  26. Res Sq. 2026 Aug 14. pii: rs.3.rs-10010180. [Epub ahead of print]
    Site-specific N6-methyladenosine fine tunes CTCF/cohesin-defined enhancer-promoter interactions and oncogenic transcription program.
    Suming Huang, Huacheng Luo, Karina Hamamoto, Jingwen Song, Tsz Kan Fung, Songtao He, Julia Lesperance, Ying Li, Mingjiang Xu, Honglin Chen, Yi Qiu, Chi Wai Eric So.
      N6-methyladenosine (m6A) of RNAs plays an important role in RNA stability and gene expression. However, it remains unknown how site-specific m6A on individual RNA is decoded to regulate chromatin architecture and transcriptional reprogramming. Here, we show that m6A modification of HOTTIP lncRNA is highly enriched in acute myeloid leukemia (AML) patients carrying MLL-rearrangement (MLLr+) or NPM1C+-mutation and regulates RNA-dependent CTCF/cohesin function. Site-specific removal/blockage of m6A on HOTTIP by CRISPR-dCas13-ALKBH5 or steric ASO blockage disrupts HOTTIP-associated R-loop formation and CTCF occupancies at HOTTIP/CTCF co-occupied TAD boundaries, leading to impaired CTCF-defined enhancer/promoter loops and HOTTIP-driven stem-cell-like transcription programs. Functionally, site-specific removal of m6A on HOTTIP impairs leukemic-stem-cell initiation/proliferation that mitigates MLLr+-driven AML severity. Targeted recruitment of RAD21 to the erased HOTTIP m6A site partially rescues CTCF-mediated enhancer/promoter interactions and HOTTIP-driven transcription, reversing the m6A depletion-associated anti-leukemic effects. Our data reveals a direct mechanistic interplay between site-specific RNA m6A modification and CTCF/cohesin-driven chromatin architecture to drive oncogenic transcription networks and leukemogenesis.
    DOI:  https://doi.org/10.21203/rs.3.rs-10010180/v1
  27. Toxicol Appl Pharmacol. 2026 Oct 05. pii: S0041-008X(26)00365-0. [Epub ahead of print] 118069
    METTL3-mediated m6A modification of PARP2 accelerates hepatocellular carcinoma progression.
    Mengke Li, Yan Zhao, Yuan Li.
      Hepatocellular carcinoma is a common primary liver cancer with high death rate worldwide. Poly ADP-ribose polymerase 2 (PARP2) has been reported to promote hepatocellular carcinoma cell growth. In this study, we aimed to explore the role of PARP2 in the progression of hepatocellular carcinoma and the underlying mechanisms at the transcriptional modification level. The protein expression of PARP2, methyltransferase-like 3 (METTL3), insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), and IGF2BP3 was determined by western blotting. MTT assay was utilized to measure cell viability. Apoptosis was evaluated by flow cytometry. Transwell invasion assay was conducted to evaluate cell invasion. MeRIP-qPCR, RIP-qPCR, and RNA stability analysis were performed to identify whether METTL3, IGF2BP2, and IGF2BP3 regulate the N6-methyladenosine (m6A) modification of PARP2. Results showed that PARP2 was highly expressed in hepatocellular carcinoma and related to its poor prognosis. Knockdown of PARP2 induced apoptosis and suppressed the viability and invasion in hepatocellular carcinoma cells. METTL3 expression was increased in hepatocellular carcinoma and positively associated with PARP2 expression. METTL3 regulated PARP2 expression by modulating its m6A modification. Moreover, PARP2 was recognized by the m6A "readers" IGF2BP2 and IGF2BP3. The effects of METTL3 knockdown on the malignant behaviors of hepatocellular carcinoma cells were reversed by PARP2 overexpression in vitro. Also, METTL3 depletion repressed tumor growth by regulating PARP2 expression in hepatocellular carcinoma xenograft mice in vivo. Our findings indicate that METTL3-mediated PARP2 m6A modification plays a vital tumor-promoter role in hepatocellular carcinoma progression.
    Keywords:  Hepatocellular carcinoma; METTL3; PARP2; m6A modification
    DOI:  https://doi.org/10.1016/j.taap.2026.118069
  28. J Cell Sci. 2026 Oct 01. pii: jcs264817. [Epub ahead of print]139(19):
    Responses to endoplasmic reticulum stress at a glance.
    Eric Chevet, Céline Philippe, Tony Avril, Elodie Lafont.
      The endoplasmic reticulum (ER) is the gateway to the eukaryotic protein secretory pathway. Beyond its role in protein biogenesis, it is central to Ca2+ homeostasis and lipid biosynthesis. This organelle, which can constitute more than 50% of the cellular membranes in secretory cells, is highly plastic and must adjust to intracellular or extracellular challenges to ensure proper protein secretion. ER stress, resulting from challenges such as accumulation, misfolding or aggregation of proteins or from disrupted ER lipid composition, can deleteriously affect cell function. Thus, the ER has evolved adaptive mechanisms that lead to cellular reprogramming to adjust its capacity to handle stress, including the unfolded protein response (UPR), which engages various ER quality control systems, protein degradation pathways and ER-organelle contacts. If this succeeds, the cell survives; but if it fails, cell death mechanisms are triggered. In this Cell Science at a Glance article and the accompanying poster, we summarize current knowledge on ER stress and control of the UPR in mammalian cells, highlighting aspects that require further attention. We also discuss recent insights that must be considered to better capture the full understanding of the ability of the ER to adjust to biological variation.
    Keywords:  Contact sites; Endoplasmic reticulum; Proteostasis; UPR; Unfolded protein response
    DOI:  https://doi.org/10.1242/jcs.264817
  29. Planta. 2026 Oct 08. pii: 161. [Epub ahead of print]264(5):
    Cold-sensitive chloroplast development: advances from chloroplast ribosome-deficient mutants.
    Xuan Zhao, Tonghui Wu, Ting Jia, Xueyun Hu.
       MAIN CONCLUSION: Cold-sensitive chloroplast ribosome-deficient mutants reveal that low temperature disrupts chloroplast ribosome biogenesis, chloroplast translation, and nascent polypeptide protection, thereby impairing chloroplast biogenesis and delaying chloroplast development in young leaves. In nature, cold stress commonly delays leaf greening in juvenile leaves of susceptible plant species. Accumulating evidence suggests that cold stress impairs chloroplast development, primarily by suppressing translational processes within chloroplasts, which play a pivotal role in their biogenesis. Although wild-type model plants exhibit no obvious delay in leaf greening under cold stress, numerous mutants defective in chloroplast translation display a cold-sensitive phenotype, characterized by markedly slowed greening of newly emerged leaves. Investigating these mutants provides valuable insights into the mechanisms underlying cold-sensitive chloroplast development, thereby offering potential strategies to improve chloroplast biogenesis in plants impaired by low-temperature conditions. This review summarizes recent advances in the analysis of chloroplast ribosome-defective mutants, which exhibit low-temperature-induced defects in early chloroplast development. These mutants have been classified into two categories based on their functional sites, including chloroplast ribosome biogenesis, and chloroplast translation and nascent polypeptide protection. We also summarize the mechanisms underlying the impact of low temperature on chloroplast development, as revealed through the study of chloroplast translation-defective mutants. Finally, based on current research findings, we propose strategies to protect the development of cold-sensitive chloroplasts and highlight the major unresolved questions and future directions in this field of study.
    Keywords:  Chloroplast development; Chloroplast ribosome biogenesis; Chloroplast translation; Cold stress
    DOI:  https://doi.org/10.1007/s00425-026-05173-x
  30. Mol Cell. 2026 Oct 09. pii: S1097-2765(26)00665-9. [Epub ahead of print]
    40S ribosome remodeling triggers 18S rRNA U-tailing and DIS3L2-dependent decay.
    Akruti Shah, Aaztli R Coria, Jennifer T Miller, Emilien Orgebin, Wilfried Guiblet, Acong Yang, Shuo Gu, Colin Chih-Chien Wu.
      Eliminating defective ribosomes through quality control is essential for accurate protein synthesis. However, the mechanisms that commit defective ribosomal subunits to decay remain poorly defined. Here, we identify a tandem mechanism in which ubiquitin-dependent ribosome remodeling and 18S rRNA uridylation lead to 40S ribosomal subunit decay. Specifically, we use an in vitro reconstitution system to show that the atypical kinase RIOK3 remodels 40S ribosomal subunits, thereby exposing the 3' end of 18S rRNA. Nanopore direct RNA sequencing reveals that this remodeling event promotes oligo-uridylation, generating uridylated 18S rRNA decay intermediates. Uridylated 18S rRNA is further degraded by the 3'-5' exoribonuclease DIS3L2. Moreover, DIS3L2-mediated exoribonucleolytic cleavage triggers endoribonucleolytic decay of the 18S rRNA, amplifying turnover. Together, our findings define a stepwise mechanism in which ribosome remodeling and RNA tailing commit defective 40S subunits to elimination, establishing a mechanistic framework for ribosome surveillance in mammalian cells.
    Keywords:  18S rRNA decay; DIS3L2; RIOK3; RNF10; TUT4/7; ribosome turnover; uridylation
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.022
  31. PLoS Pathog. 2026 Oct;22(10): e1014682
    Active transcriptome remodeling underlies antimony-induced drug tolerance in persister-like Leishmania parasites.
    Eyson Quiceno, Cristian Camilo Rodríguez-Almonacid, Khalid Omeir, Jacob Ancira, Caleb Phillips, Zemfira N Karamysheva.
      Persistence - characterized by the transient ability of subpopulations of Leishmania parasites to survive exposure to drugs - is a major driver of treatment failure and clinical relapses in leishmaniasis. Persisters are characterized by non-dividing or slow-growing state and increased drug tolerance. However, the molecular mechanisms governing formation of persisters remain poorly understood in Leishmania parasites. Here, we developed a model to explore persistence in Leishmania mexicana. Viable promastigote persister-like subpopulations were enriched using Ficoll density gradient centrifugation following lethal exposure to potassium antimonyl tartrate (PAT) that killed 80% of parasites. The surviving parasites exhibited delayed growth in drug-free medium that is characteristic for persisters, and higher drug tolerance upon rechallenge. Transcriptomic profiling across acute stress, drug-free recovery, and rechallenge phases revealed a global remodeling in persister-like cells under all tested conditions. Induction was characterized by downregulation of several biological processes and a robust upregulation of nucleolar pathways, supporting epitranscriptomic changes during the formation of persister-like cells. Upon drug removal, this profile rapidly reverted, initiating ribosome biogenesis to exit latency and resume proliferation. Resuscitation phase exhibited active protein synthesis and upregulation in biological processes associated with metabolic and mitochondrial functions. Furthermore, persister-like parasites displayed distinct drug response profiles compared to parental parasites by rapidly implementing a highly conserved, coordinated survival reprogramming, where 316 genes were uniquely downregulated, and 241 genes were upregulated. The distinct features of the drug response in rechallenged persister-like cells were characterized by the downregulation of mitochondrial function and protein synthesis to induce dormant state, and the upregulation of drug-response and stress-tolerance genes to survive immediate toxicity. In contrast, parental parasites displayed a broad and disorganized drug response. Additionally, rechallenged persisters exhibited distinct transcriptomic features that transiently phenocopies stable genetic resistance. This pre-adapted state is characterized by the targeted upregulation of epigenetic and epitranscriptomic modulators, heavy metal transporters, and catabolic enzymes to maintain viability. These findings demonstrate that drug persistence in Leishmania is not merely a metabolic collapse, but rather a sophisticated survival strategy involving active transcriptome remodeling, downregulation of translation and epigenetic/epitranscriptomic changes. This transient state constitutes an initial evolutionary step toward permanent drug resistance and highlights new molecular vulnerabilities for therapeutic interventions aimed at preventing clinical relapse.
    DOI:  https://doi.org/10.1371/journal.ppat.1014682
  32. Neuron. 2026 Oct 09. pii: S0896-6273(26)00683-5. [Epub ahead of print]
    Tau phosphorylation from neuronal adaptation to Alzheimer's disease.
    Ryan Trouvé, Patrik Verstreken, Marieke M B Hoekstra.
      Tau phosphorylation is classically associated with neurodegeneration, yet similar phosphorylation patterns emerge during physiological states and acute stress responses. How these overlapping patterns of phosphorylated Tau (pTau) relate to neuronal adaptation and Alzheimer's disease pathology remains unresolved. We synthesize findings from human to rodent and fly brains and from neuronal cell models, across neurodevelopment, sleep, hibernation, cellular stress, and disease. Across these contexts, pTau changes are associated with altered Tau localization and functions involving synaptic transmission, mitochondrial activity, RNA metabolism, and genomic integrity. Physiological and acute stress responses are generally transient and reversible, whereas aging, repeated stress, and amyloid-β-associated stress can promote persistent pTau accumulation, impaired clearance, aggregation, and neurodegeneration. We propose that pathological Tau phosphorylation reflects dysregulation of a shared adaptive response rather than activation of an entirely distinct pathway. The critical determinants may be phosphorylation persistence, subcellular localization, proteoform composition, and the capacity to restore Tau homeostasis.
    Keywords:  Alzheimer's disease; Tau; Tau phosphorylation; physiological role; stress response
    DOI:  https://doi.org/10.1016/j.neuron.2026.08.032
  33. Bioorg Chem. 2026 Oct 05. pii: S0045-2068(26)01122-3. [Epub ahead of print]183 110586
    Novel hybrid salicylaldehyde-sulfonamide schiff bases elicit an ISR-associated transcriptomic response and suppress cancer cell survival.
    Mohamed A Eltokhy, Moustafa S Abusaif, Eman A Fayed, Ahmed Ragab, Sahar Radwan, Yousry A Ammar, Sanjay K Srivastava.
      In this study, we describe the rational design, synthesis, and biological evaluation of a novel series of salicylaldehyde-derived sulfonamide Schiff base hybrids. Eight compounds (C3-C10) were synthesized via condensation of 3-formyl-4-hydroxybenzenesulfonyl chloride with diverse primary amines and extensively characterized using IR, NMR, and MS/MS. Synthesized compounds were evaluated for their cytotoxicity in a variety of pancreatic, breast, colorectal, hepatic and ovarian cancer cell lines, and compound C5 was identified as the lead candidate, with an IC₅₀ ranging 4.1-75 μM across the complete cancer-cell panel. Interestingly, C5 exhibited lower cytotoxicity towards the normal nonmalignant cells as compared to cancer cell lines indicating selectivity. Transcriptomic profiling (RNA-seq) in SUIT-2 pancreatic cancer cells treated with C5 identified a gene expression signature that was associated with the activation of integrated stress response (ISR) through upregulation of key stress-associated genes, alongside suppression of oncogenes. Gene ontology and pathway enrichment analysis demonstrated significant modulation of ER stress, unfolded protein response, amino acid metabolism, and lipid metabolic pathways, indicating metabolic reprogramming and stress adaptation. Long non-coding RNA (lncRNA) profiling identified treatment-associated changes in stress- and cancer-related transcripts. Taken together, these findings identify C5 as a promising lead compound with anticancer activity associated with modulation of cellular stress-response pathways and metabolic pathways.
    Keywords:  Anticancer; Cytotoxic screening; Drug discovery; Hybrid synthesis; Medicinal chemistry; Organic synthesis; RNA Seq; Salicylaldehyde; Schiff's base; Sulfonamide
    DOI:  https://doi.org/10.1016/j.bioorg.2026.110586
  34. PLoS Pathog. 2026 Oct 06. 22(10): e1014624
    GlRac regulates an ATG8-independent autophagy-like pathway in Giardia lamblia.
    Angélica Hollunder Klippel, Corryn Newman-Boulle, Grant Reed, Dule Dule, Saanya Kedia, Martin T Kelty, Wai Pang Chan, Han-Wei Shih, Alexander R Paredez.
      Autophagy is a conserved catabolic process essential for cellular homeostasis and adaptation to nutrient stress. The protozoan parasite Giardia lamblia lacks most canonical autophagy-related (ATG) genes, including the hallmark ATG8, raising longstanding questions about whether this deeply divergent parasite can perform autophagy. Here, we identify an ATG8-independent autophagy-like pathway in Giardia regulated by GlRac, the parasite's sole Rho family GTPase. GlRac-positive double-membrane compartments are induced by encystation and nutrient depletion, and their abundance rapidly declines following amino acid replenishment but is unaffected by glucose, indicating amino acid-specific regulation. Giardia Target of Rapamycin (GTOR) levels decrease during nutrient depletion, and GTOR knockdown increases compartment abundance, identifying GTOR as a negative regulator of compartment formation and linking this pathway to nutrient sensing. Time-lapse microscopy revealed that these compartments form through linear and cup-shaped intermediates before becoming spherical and are subsequently cleared upon nutrient replenishment. Of nine putative ATG orthologs examined, none localized as specifically as GlRac to these structures, supporting the existence of a highly divergent pathway. Nevertheless, the compartments exhibit multiple conserved autophagy-associated features, including double-membrane morphology, actin recruitment, acidification, and cysteine protease activity. Pharmacological inhibition of cysteine proteases with E-64d or blocking V-ATPase-mediated acidification with concanamycin A promotes compartment accumulation, consistent with continuous degradative turnover. GlRac regulates compartment biogenesis bidirectionally: constitutive activation increases compartment abundance and size, whereas knockdown reduces them. Finally, quinacrine, an FDA-approved antigiardial drug that accumulates in acidic organelles, perturbs GlRac-positive compartments, consistent with its reported effects on autophagy in other eukaryotes, raising the possibility that this pathway contributes to parasite fitness. Together, these findings establish GlRac as a central regulator of an ATG8-independent autophagy-like pathway in Giardia and demonstrate that this parasite retains key structural, regulatory, and degradation-associated features of autophagy despite the apparent absence of most canonical ATG machinery.
    DOI:  https://doi.org/10.1371/journal.ppat.1014624
  35. RNA. 2026 Oct 08. pii: rna.081090.126. [Epub ahead of print]
    Optimization of Circle-Seq improves transcription error profiling and transcriptome representation.
    Laura Deus Ramirez, Matthew Brandon Cooke, Jennifer Anne Halliday, Christophe Herman.
      Errors in transcription generate transient RNA variants that are amplified through translation, with potential consequences for cellular phenotypes and RNA-based therapeutics. Accurate detection of these rare events relies on high-fidelity sequencing approaches such as Circle-Seq, but technical artifacts introduced during RNA preparation can distort error profiles and frequencies. Here, we systematically evaluate the impact of bacterial RNA sample preparation on Circle-Seq outputs. We show that RNA extraction and ribosomal RNA depletion introduce artifactual oxidative damage signatures, particularly C>U and G>A substitutions, that inflate apparent transcription error rates. Optimized mRNA preparation conditions substantially reduce these artifacts. In addition, we identify an RNase III fragmentation bias caused by its preference for structured RNAs, resulting in uneven transcriptome coverage. Chaotropic monovalent ions mitigate this bias and improve coverage uniformity. Finally, our optimized protocol captured, with improved accuracy, the frequency and spectrum of transcription errors in absence of the transcription fidelity factor GreA. Together, these results define the technical limitations of Circle-Seq and provide practical solutions to improve the accuracy and interpretability of transcription error measurements in bacterial systems.
    Keywords:  Circle-seq; Phenotypic variability; RNA error; Transcription Fidelity
    DOI:  https://doi.org/10.1261/rna.081090.126
  36. Front Genome Ed. 2026 ;8 1818972
    Precision engineering of upstream open reading frames for translational regulation and crop improvement.
    Linjie Xu, Jiaojiao Ren, Jinjie Zhu.
      Upstream open reading frames (uORFs) are pervasive cis-regulatory elements in the 5'untranslated regions (UTRs) of eukaryotic mRNAs that modulate translation of downstream main open reading frames (mORFs) by shaping ribosome scanning, initiation, and reinitiation. By operating downstream of transcription, uORFs enable fine-scale control of protein abundance, offering a distinctive regulatory layer for precise tuning of gene expression in plants. Recent advances in ribosome profiling, translation initiation-site mapping, peptidomics, computational annotation, and genome editing have expanded the discovery, functional validation, and targeted manipulation of plant uORFs. In this review, we summarize current understanding of uORF-mediated translational regulation, discuss computational and experimental approaches for candidate identification and functional validation, and highlight genome-editing strategies used to modify endogenous uORFs in crops. We further synthesize representative studies in which uORF editing has been used to modulate metabolic traits, plant development, nutritional quality, and responses to biotic and abiotic stresses. Collectively, available evidence suggests that uORF manipulation can support quantitative and context-dependent trait modulation, in some cases preserving basal gene function and reducing growth fitness penalties. We further discuss outstanding challenges, including transcript isoform complexity, context-dependent translational effects, and the need for validation across diverse genetic and environmental backgrounds. Overall, uORF engineering represents a promising strategy for translational fine-tuning of plant gene expression, with potential implications for crop improvement and sustainable agriculture.
    Keywords:  crop improvement; fine-tuning; genome editing; translational control; uORFs
    DOI:  https://doi.org/10.3389/fgeed.2026.1818972
  37. Mol Cancer Res. 2026 Oct 09.
    tRF-3021a Promotes Apoptosis Resistance and Global Protein Synthesis in Cancer Cell Lines.
    Fatemeh Esmaeili, Kumarjeet Banerjee, Ajay Chatrath, Divya Sahu, Yoshiyuki Shibata, Shekhar Saha, Pankaj Kumar, Zhangli Su, Anindya Dutta.
      tRNA-derived fragments (tRFs) are a relatively recently discovered class of small RNAs implicated in gene-regulation, particularly behaving as microRNA to degrade target mRNAs with seed-sequence matches, but there have been very few reports of a clear phenotypic role of these small RNAs in cancer cell growth and other properties. Here we report that in three different cancer cell lineages, tRF-3009a, tRF-3021a and tRF-3030a are required for cell invasion and migration. Of the three tRFs, tRF-3021a was uniquely required for cell proliferation and suppression of apoptosis. Interestingly, tRF-3021a knockdown decreases global protein synthesis prior to and independent of apoptosis in a number of cancer cell lines of different lineages. Mutation of tRF-3021a shows that the effect on protein synthesis is very dependent on specific sequences in the tRF. RNA-seq reveals that the results cannot be explained by tRF-3021a decreasing the levels of target mRNAs that carry seed sequence matches with the tRF. These data indicate that tRF-3021a supports cancer cell survival and particularly protein synthesis while promoting cellular invasion and migration. Implications: tRF-3021a promotes malignant cell phenotypes, sustains global protein synthesis and prevents spontaneous apoptosis.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-26-0126
  38. Bioinformatics. 2026 Oct 07. pii: btag745. [Epub ahead of print]
    VAEBAC: A representation-learning framework for proteome-scale prediction of amyloidogenic proteins and functional stratification of nucleic-acid-binding proteins.
    Muhammad Uzair Ashraf, Owais Ahmad, Rizwan Hasan Khan.
       MOTIVATION: Nucleic-acid-binding proteins (NABPs) govern transcription, replication and genome organization, yet the distribution of aggregation susceptibility within regulatory proteomes remains unresolved. Here, we systematically examine amyloidogenic potential across the nucleic-acid-binding proteomes of four phylogenetically diverse organisms-Escherichia coli, Bacillus subtilis, Saccharomyces cerevisiae and Homo sapiens-spanning prokaryotes and eukaryotes, to determine whether aggregation-prone sequence architectures are selectively constrained within transcriptional networks.
    RESULTS: Using VAEBAC, a representation-learning framework that integrates large-scale amyloid-family sequences with experimentally validated annotations, we performed proteome-scale prediction of amyloidogenicity across nucleic-acid-binding proteins in each organism. Predicted amyloidogenic proteins were consistently and significantly enriched in Gene Ontology categories associated with regulation of DNA-templated transcription, RNA biosynthesis, and gene expression across all four organisms, a pattern validated using three independent annotation tools. Fisher's exact test confirmed significant enrichment of amyloidogenic NABPs among transcription regulators in eukaryotic proteomes. Residue-level mapping demonstrated spatial separation between predicted aggregation-prone regions and DNA-binding interfaces, suggesting structural compatibility between regulatory function and conditional aggregation. Experimental validation confirmed fibrillar assembly of selected proteins. These findings support a conserved model in which aggregation susceptibility is functionally stratified across transcriptional regulatory tiers rather than uniformly suppressed within NABPs, a principle conserved across 3.5 billion years of evolution.
    AVAILABILITY AND IMPLEMENTATION: VAEBAC is freely accessible at https://www.vaebac.com.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    Keywords:  amyloid prediction; cross-organism conservation; machine learning; nucleic-acid-binding proteins; protein aggregation; transcriptional regulation; variational autoencoder
    DOI:  https://doi.org/10.1093/bioinformatics/btag745
  39. Cell Rep. 2026 Sep 22. pii: S2211-1247(26)01166-6. [Epub ahead of print]45(10): 118087
    ZNF121 recruits YTHDF2 to modulate mRNA stability.
    Giovanni L Burke, Syed Nabeel-Shah, Shuye Pu, Nujhat Ahmed, Shahir M Morcos, James D Burns, Ahmed Abosen, Guoqing Zhong, Eric I Campos, Jack F Greenblatt.
      N6-methyladenosine (m6A) is the most abundant mRNA modification, regulating gene expression through binding of reader proteins, such as YTHDF2, which promote mRNA decay. Previous studies indicate YTHDF2 has relatively weak intrinsic RNA-binding affinity, suggesting additional factors may facilitate RNA binding. Here, we show that the C2H2-Zinc Finger protein, ZNF121, binds mRNA in cells and physically interacts with YTHDF2 in the cytoplasm. We demonstrate that ∼80% of ZNF121-bound mRNAs are also YTHDF2 targets, and that their binding sites are highly correlated. Loss of ZNF121 impairs YTHDF2 binding to shared targets, mostly independent of m6A, increasing stability of a subset of targets. Co-regulated transcripts are enriched for cell-cycle-related pathways, and ZNF121 depletion elevates expression of the oncogene MDM2, implicating ZNF121 in growth control and the DNA damage response. Our findings identify ZNF121 as a cofactor that enhances YTHDF2-mediated mRNA regulation, highlighting a different mechanism for YTHDF2 in regulating mRNA decay.
    Keywords:  C2H2-zinc finger; CP: molecular biology; RNA binding; YTHDF2; ZNF121; m6A; mRNA stability
    DOI:  https://doi.org/10.1016/j.celrep.2026.118087
  40. Nucleic Acids Res. 2026 Sep 22. pii: gkag941. [Epub ahead of print]54(18):
    Establishing the molecular basis for MDA5 mutation-linked autoimmunity.
    Ling Xu, Harim Jang, Kevin Chung, Rong Guo, Alisia Pan, Anna Marie Pyle.
      Melanoma differentiation-associated protein 5 (MDA5), a member of the RIG-I-like receptor family, is a cytoplasmic sensor essential for innate antiviral immunity. MDA5 distinguishes viral RNA from host RNA in part through its ATP hydrolysis activity, which promotes filament turnover on shorter endogenous double-stranded RNAs (dsRNAs). Here, we show that the gain-of-function T331I disease-linked mutation within the ATP-binding pocket disrupts this balance, resulting in constitutive interferon signaling. Through a combination of cryo-electron microscopy (cryoEM), biochemical assays, and cellular analyses, we reveal the extensive network of interactions that precisely position ATP for catalysis in the wild-type MDA5 ATP-binding pocket and also demonstrate that the T331I mutation impairs ATPase activity, thereby stabilizing MDA5-dsRNA complexes and leading to aberrant immune activation. These findings elucidate how MDA5 ATPase activity regulates antiviral specificity and prevents autoimmunity by controlling filament stability and downstream signaling, offering a mechanistic molecular explanation for disease pathogenesis.
    DOI:  https://doi.org/10.1093/nar/gkag941
  41. Biochem Biophys Res Commun. 2026 Sep 21. pii: S0006-291X(26)01368-9. [Epub ahead of print]839 154602
    SUMOylation and palmitoylation in metastatic prostate cancer: A compartment-based framework for nuclear and membrane adaptation.
    Shuangyu Ji, Shiyu Li, Yong Wei, Qingyi Zhu.
      Metastatic prostate cancer remains lethal despite treatment intensification, in part because tumor cells can adopt rapid and reversible states that are not fully explained by genomic alterations. Post-translational modifications provide a dynamic regulatory layer by changing protein activity, localization, stability, and molecular interactions. This Review evaluates SUMOylation and reversible S-palmitoylation as compartment-biased systems that regulate complementary dimensions of metastatic adaptation. SUMOylation has a comparatively mature mechanistic foundation in androgen receptor transcription, chromatin organization, DNA damage responses, tumor-suppressor function, and stress adaptation. The prostate cancer palmitoylation literature is smaller, but it identifies discrete mechanisms involving androgen-regulated protein acylation, receptor and cytoskeletal signaling, lipid metabolism, ferroptosis, and immune regulation. We propose that these modifications converge functionally at pathway and cell-state levels rather than forming an established biochemical circuit. Their shared outputs may include treatment persistence, metabolic adaptation, cellular plasticity, invasion, and tumor-microenvironment interactions. Translation should therefore prioritize disease-specific enzyme-substrate dependencies, direct measures of target engagement, and mechanistically matched combinations with established therapies rather than global or simultaneous inhibition of both modification systems.
    Keywords:  Androgen receptor; Castration-resistant prostate cancer; DNA damage response; Metastatic prostate cancer; Palmitoylation; Post-translational modification; SUMOylation; Tumor adaptation
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154602
  42. Exp Gerontol. 2026 Oct 06. pii: S0531-5565(26)00326-8. [Epub ahead of print]225 113347
    Differences of oxidative damage in the brain of short- and long-lived Nothobranchius furzeri strains.
    Julien Lehmann, Oksana Savel, Melissa M Page.
       BACKGROUND: The turquoise killifish (Nothobranchius furzeri), while being reported as the vertebrate with the shortest lifespan in captivity, includes many strains that diverge in their lifespans. Underlying mechanisms for these differences are believed to occur in part at the level of mitochondria, which contribute to aging through their role in energy metabolism and oxidative stress.
    METHODS: We used the short-lived GRZ strain and the longer-lived MZCS-222 strain to determine whether lifespan divergence is associated with distinct mitochondrial maintenance, oxidative damage, and mitigating pathways in the brain. Killifish brain homogenates were analyzed through western blots, RT-qPCR and enzymatic assays.
    RESULTS: In these two strains, we report that mitochondrial content declined with age in GRZ individuals, whereas it remained stable in MZCS-222 fish. The longer-lived strain also exhibited age-related increases in SOD1 and SOD2 at the protein level, suggesting enhanced antioxidant defenses. In contrast, GRZ showed an early upregulation of pink1 and bax, consistent with putative increased mitophagy and apoptotic signaling in response to mitochondrial stress, whereas MZCS-222 showed an increase in pink1 expression while maintaining stable levels of bax, indicating a possible control of mitochondrial quality through mitophagy only.
    CONCLUSION: Together, these findings indicate that lifespan divergence in N. furzeri is associated with distinct mitochondrial aging trajectories, supporting that enhanced antioxidants defenses and mitochondrial quality control contribute to the preservation of brain mitochondrial homeostasis and increased longevity.
    Keywords:  Brain; Lifespan; Long-lived species; Mitochondrial dysfunction; Nothobranchius furzeri; Oxidative damage; Short-lived species
    DOI:  https://doi.org/10.1016/j.exger.2026.113347
  43. Trends Parasitol. 2026 Sep 22. pii: S1471-4922(26)00285-0. [Epub ahead of print]
    Starving but surviving: a new RNA switch rewires parasite metabolism.
    Janina Jocks, Frank Seeber, Martin Blume.
      Intracellular Toxoplasma gondii parasites face severe metabolic stress during high-density infection. Giuliano et al. identify a novel mechanism involving the protein 'T. gondii parasite response to oxidation' (TgPRO). This RNA-binding protein regulates the translation of mRNAs vital for Fe-S cluster assembly and mitochondrial metabolism. TgPRO is crucial for oxygen-dependent adaptation and for ensuring optimal in vivo parasite replication.
    Keywords:  Toxoplasma gondii; crowding; gene regulation; metabolic regulation; oxidative stress
    DOI:  https://doi.org/10.1016/j.pt.2026.09.014
  44. Diabetes. 2026 Oct 06. pii: db260413. [Epub ahead of print]
    Mitochondrial YME1L Restrains GRP75-Dependent ISR Activation to Prevent Podocyte Senescence in Diabetic Kidney Disease.
    Qianqian Yang, Yiyuan Zhang, Yaowu Zhang, Hui Zhang, Liqin Zhang, Xiaobo Zhang, Yong Xu, Qijing Wu.
       ARTICLE HIGHLIGHTS: Loss of YME1L promotes podocyte senescence in diabetic kidney disease. YME1L deficiency induces sustained maladaptive integrated stress response activation. YME1L interacts with and regulates mitochondrial GRP75 homeostasis. GRP75 accumulation drives persistent integrated stress response activation and mitochondrial dysfunction.
    DOI:  https://doi.org/10.2337/db26-0413
  45. J Vis Exp. 2026 Oct 06.
    METTL3-Associated FOXD1 Regulation Promotes Lung Squamous Cell Carcinoma Progression: A Multimodel Experimental Approach.
    Quzong Deji, Danzeng Awang, Kaizhong Wang, Lanzi Gongga, Shiyun Feng, Hui Zhao, Yuhang Shang, Qisheng Pang, Guangchao Lv.
      Lung squamous cell carcinoma (LUSC) has limited treatment options, motivating investigation of molecular pathways that support tumor-cell growth. Forkhead box D1 (FOXD1) expression was assessed using gene expression profiling interactive analysis (GEPIA), quantitative reverse-transcription polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry in paired tissues and cell lines. FOXD1 or methyltransferase-like 3 (METTL3) was depleted in LUSC cells, and cell viability, apoptosis, migration, global N6-methyladenosine (m6A), transcript stability, and protein stability were evaluated. A FOXD1-knockdown xenograft model tested the in vivo role of FOXD1; METTL3 was not manipulated in animals. FOXD1 expression was higher in LUSC tissues and cells than in corresponding controls. FOXD1 knockdown reduced viability and migration, increased apoptosis, and suppressed xenograft growth. METTL3 expression correlated with FOXD1 in paired LUSC tissues. In cultured cells, METTL3 knockdown lowered global m6A and FOXD1 abundance, whereas FOXD1 re-expression partially rescued the associated phenotypes. Actinomycin D, cycloheximide, and MG132 assays were consistent with METTL3-associated changes in FOXD1 RNA and protein stability. These data support a functional association between METTL3 and FOXD1 in LUSC cells. In vivo, FOXD1 knockdown suppressed xenograft growth and reduced Ki-67 staining, establishing FOXD1 as a promoter of xenograft growth. Direct METTL3-FOXD1 binding, site-specific m6A modification, reader dependence, and in vivo validation of the complete METTL3-FOXD1 pathway remain to be established.
    DOI:  https://doi.org/10.3791/73588
  46. RNA. 2026 Oct 09. pii: rna.081135.126. [Epub ahead of print]
    Preferential G3BP1-induced condensation of DNA-RNA mixtures from stress granules over RNA or double-stranded DNA.
    Natalia A Demeshkina, Adrian R Ferré-D'Amaré.
      G3BP1 is a regulator of stress granule assembly capable of driving condensation of RNA in vitro. Recently, we purified stress granule cores from yeast and mammalian cells, and found that in addition to RNA and proteins, they contain large amounts of circular double-stranded DNA (dsDNA). Since G3BP1 has been implicated in DNA-RNA heteroduplex resolution, we compared the ability of G3BP1 to drive condensation of cytoplasmic RNA, circular cytoplasmic dsDNA, and total nucleic acids (comprising both, circular dsDNA and RNA) extracted from purified stress granule cores of HEK293T cells. Imaging under near-physiologic conditions (1.7 mM MgCl2, no crowding agents, 0.1 ng/μL nucleic acids) revealed that G3BP1 most effectively induces condensation of the DNA-RNA mixture from stress granule cores. Comparison of the disruption of these condensates by treatment with RNase A, DNase, or RNase H further shows that they are especially susceptible to the latter two. The sensitivity to DNase and RNase H of G3BP1-induced condensates of the stress granule-derived nucleic acid mixtures underscores the importance of DNA in these cytoplasmic assemblies.
    Keywords:  DNA-RNA heteroduplexes; HEK293T cells; Stress granules; circular DNA; eccDNA
    DOI:  https://doi.org/10.1261/rna.081135.126
  47. PLoS One. 2026 ;21(10): e0358942
    A catalog of mRNAs transferred from males to females during mating in Drosophila arizonae and D. mojavensis.
    Juan Hurtado, Carson W Allan, Sergio Castrezana, Jeremy M Bono, Luciano M Matzkin.
      mRNA is a common component of male ejaculates across diverse organisms, yet whether these male-derived mRNAs (mdRNAs) serve biological functions in females or represent incidental byproducts of ejaculate composition remains unresolved. Recent work in Drosophilq arizonae demonstrated that mdRNAs are translated by female reproductive tract cells into proteins, and that genes encoding them have functional postmating effects, suggesting that at least some mdRNAs are biologically important. A systematic characterization of the mdRNA repertoire in this species is therefore a necessary next step. Here we present a catalog of mdRNAs in D. arizonae and its sister species D. mojavensis, identified through RNA-seq profiling of the female reproductive tract following heterospecific crosses, with expression data from male reproductive tract organs to classify candidates by tissue of origin. We identified 270 candidate mdRNAs whose abundance in the reproductive tract of mated females correlates with expression in testes, sperm-filled seminal vesicles, and accessory glands, consistent with multiple tissues contributing to the pool of mdRNAs. Functional enrichment analyses reveal overrepresentation of ribosomal proteins, suggesting potential roles in translational regulation within the female reproductive tract. To investigate how sperm-associated mdRNAs might become available for translation in the female reproductive tract, we generated a GFP-tagged sperm line and tracked sperm fate following mating. A substantial proportion of transferred sperm became trapped within the insemination reaction mass that forms in the uterus during copulation, possibly releasing RNA into the female reproductive environment. This catalog provides a foundation for future studies on the biological significance of mdRNAs.
    DOI:  https://doi.org/10.1371/journal.pone.0358942
  48. Diabetologia. 2026 Oct 03.
    Adipocyte-derived exosomal ANGPTL2 promotes beta cell dysfunction via the EIF2α/ATF4/CHOP stress pathway in mice.
    Xiaoqi Zhong, Qiuna Wei, Qi Cheng, Mingwen Weng, Shengxin Wang, Hong Chen, Yuting Ruan.
       AIMS/HYPOTHESIS: Obesity-associated lipotoxicity drives beta cell failure in type 2 diabetes, but the adipose-to-islet signals that promote beta cell dysfunction remain incompletely defined. We hypothesised that angiopoietin-like protein 2 (ANGPTL2) carried by lipotoxic adipocyte-derived exosomes contributes to adipose-to-islet signalling that impairs beta cell function.
    METHODS: Exosomes from palmitate- or PBS-treated 3T3-L1 adipocytes were applied to MIN6 cells and primary mouse islets to assess beta cell function and identity. In vivo, mice underwent adipose-specific Angptl2 knockdown under high-fat diet (HFD) feeding, followed by metabolic phenotyping and assessment of beta cell function. Adipose-derived exosomes from HFD-fed mice with or without adipose Angptl2 knockdown were injected into normal-chow-fed recipient mice, and endocrine marker composition and islet secretory function were evaluated. Mechanistic studies in MIN6 cells used co-immunoprecipitation, pharmacological rescue experiments and Eif2α (also known as Eif2s1) knockdown to interrogate stress signalling.
    RESULTS: Exosomes derived from palmitate-treated adipocytes were efficiently internalised by beta cells and resulted in impaired insulin content and secretion, accompanied by reduced beta cell identity markers and induction of dedifferentiation signatures. ANGPTL2 was enriched in lipotoxic adipocyte-derived exosomes and accumulated in beta cells in an exosome-dependent manner. Angptl2 silencing in adipocytes lowered exosomal ANGPTL2 and mitigated islet dysfunction in vitro. In vivo, adipose-specific Angptl2 knockdown reduced islet ANGPTL2 without changing islet Angptl2 mRNA and improved glucose tolerance, with the AUC of the IPGTT decreasing from 2300.2 ± 165.5 to 1583.7 ± 88.8 mmol/l × min (mean ± SD). In adipose-exosome transfer experiments, recipients of HFD-short hairpin (sh)Angptl2-exosome (Exo) showed lower islet ANGPTL2 abundance and improved ex vivo islet glucose-stimulated insulin secretion (GSIS), with stimulated insulin secretion increasing from 6.0 ± 0.3% (mean ± SD) in the HFD-sh-negative control (NC)-Exo group to 10.9 ± 0.6% in the HFD-shAngptl2-Exo group. Mechanistically, ANGPTL2 associated with eukaryotic translation initiation factor 2α (EIF2α) and increased protein kinase R-like endoplasmic reticulum kinase (PERK)-associated EIF2α by approximately 2.8-fold, whereas this difference was lost after further normalisation to input EIF2α, supporting a substrate-availability model. PERK inhibition and integrated stress response inhibitor both attenuated ANGPTL2-induced activating transcription factor-4 (ATF4)/C/EBP homologous protein (CHOP) signalling and improved GSIS.
    CONCLUSIONS/INTERPRETATION: Lipotoxic adipocyte-derived exosomes increase ANGPTL2 abundance in recipient beta cells and contribute to beta cell dysfunction and identity disruption by amplifying PERK-dependent EIF2α/ATF4/CHOP signalling. Adipose ANGPTL2 and circulating exosome-associated ANGPTL2 represent candidate targets and biomarkers for preserving beta cell function in obesity-associated dysglycaemia.
    Keywords:  ANGPTL2; Adipocyte-derived exosomes; Beta cell dysfunction; EIF2α; Lipotoxicity
    DOI:  https://doi.org/10.1007/s00125-026-06885-1
  49. bioRxiv. 2026 Aug 15. pii: 2026.08.11.744028. [Epub ahead of print]
    NMR assignments and secondary structure analysis of the human 5MP1 C-terminal domain.
    Ayşenur Şeker, Simran Anand, Assen Marintchev.
      Eukaryotic translation initiation is tightly regulated by interactions among translation initiation factors (eIFs) that ensure accurate start codon selection. The translation regulator, eIF5 mimic protein 1 (5MP1) contributes to this process by competing with eIF5 for binding to eIF2, thereby increasing the stringency of translation initiation. Despite its important regulatory role and emerging involvement in tumorigenesis, structural information on human 5MP1 remains limited. Here, we report the near-complete backbone and partial side-chain NMR resonance assignments of the C-terminal domain of human 5MP1 (residues 250-419), carrying a W404E substitution that disrupts dimerization. The WT protein forms a dimer at NMR concentrations, which increases the effective size of the protein and also causes disappearance of peaks corresponding to aminoacids at the dimer interface due to conformational exchange. Backbone resonance assignments were completed for 96.4% of the non-proline residues. Secondary structure was analyzed using Chemical Shift Index (CSI) and compared with the AlphaFold structural model. Regions of disagreement between the experimental and computational secondary structure assignments were further examined using 15 N-NOESY-HSQC spectra, allowing experimental validation of local structural features. While the AlphaFold model accurately reproduces the overall fold of the 5MP1 C-terminal domain, several localized discrepancies were identified, particularly near the N- and C-terminal regions of the domain, where experimental NMR data support alternative secondary structure assignments. These resonance assignments and experimentally validated structural features provide a foundation for future investigations of the molecular interactions, dynamics, and functions of 5MP1 in translation initiation.
    DOI:  https://doi.org/10.64898/2026.08.11.744028
  50. RNA. 2026 Oct 09. pii: rna.081162.126. [Epub ahead of print]
    PNLDC1 deadenylase affects translational rate and cell proliferation in mESCs.
    Ilias Skeparnias, Athanasios-Nasir Shaukat, Christos Katsioulas, Dimitrios Anastasakis, Katerina Grafanaki, Vasiliki Chondrou, Argyro Sgourou, Jinwei Zhang, Athanasios Papakyriakou, Constantinos Stathopoulos.
      PNLDC1 is a member of the DEDD deadenylases, known for its specificity in poly(A) tail removal during mRNA turnover. While initially characterized for its function in pre-piRNA trimming critical to spermatogenesis and transposon silencing, its broader deadenylase activity which is especially pronounced during early development and silenced during differentiation, remains poorly understood. In this study, we mapped the epigenetic regulation of Pnldc1 during mESC differentiation, uncovering its promoter methylation pattern associated with transcriptional repression. Pnldc1-knockout mESC models established via CRISPR/Cas9 were shown to retain viability and pluripotency. RNA-seq and subsequent polysome profiling revealed that Pnldc1 deficiency leads to the downregulation of gene networks involved in translation and a lower overall translational rate. Notably, PNLDC1 has been linked to epigenetic changes in various cancers and is associated with oncogenic signaling pathways. Using a homology model based on the related PARN deadenylase, we conducted virtual screening of compound libraries and selected 12 candidates for experimental testing. Experimental validation revealed that two compounds significantly impacted genes involved in stress response and signal transduction, while also suppressing aberrant proliferation. These findings highlight PNLDC1's role in regulating mRNA stability during differentiation and proliferation and as a candidate for targeted therapeutic intervention.
    Keywords:  Deadenylase; PARN; PNLDC1; mRNA turnover
    DOI:  https://doi.org/10.1261/rna.081162.126
  51. bioRxiv. 2026 Aug 11. pii: 2026.08.10.744062. [Epub ahead of print]
    Life without cytoplasm: sperm sustain protein production utilizing cytoplasmic droplets and mitochondria as translational apparatuses.
    Zhuqing Wang, Hetan Wang, Rubens Daniel Miserani Magalhães, Sheng Chen, Siying Meng, Dayton Morris, Sarah Crane, Hayden McSwiggin, Anne Elizabeth Yan, Saayli Khambekar, Brian Nguyen, Huili Zheng, Wei Yan.
      Sperm present a unique paradox: heavily compacted chromatin silences transcription, and loss of cytoplasm during spermiation eliminates the conventional translational apparatus, yet sperm require ∼10 days of protein-demanding epididymal maturation to acquire motility and fertilization competence. How sperm produce the necessary proteins has remained enigmatic. Here, we show that mammalian sperm sustain protein synthesis through a biphasic translational program. In testicular sperm, a residual cytoplasmic droplet retains the full complement of translational machinery, including ribosomes and intact tRNAs, and supports nascent protein synthesis. As sperm enter the epididymis, this droplet is progressively fragmented, and protein synthesis shifts to the midpiece, where mitochondrial translation machinery becomes active. Proteomic and functional analyses indicate that both systems contribute to sperm maturation. Inhibiting cytoplasmic translation in testicular sperm or mitochondrial translation in epididymal sperm abolishes motility. These findings reveal how cytoplasm-free sperm overcome transcriptional silence to complete maturation and support male fertility.
    Graphic Abstract:
    DOI:  https://doi.org/10.64898/2026.08.10.744062
  52. J Med Microbiol. 2026 Oct;75(10):
    Molecular remodelling of Cryptococcus neoformans during adaptation to host temperature.
    Marianna Dallastella, Isadora F Munhoz da Rocha, Bruno A A Romagnoli, Lysangela R Alves.
      Introduction. The ability of Cryptococcus neoformans to adapt to host temperature is an important feature of its pathogenic potential and requires extensive cellular remodelling.Hypothesis/Gap Statement. Although C. neoformans undergoes substantial molecular changes at host temperature, the extent to which transcriptomic and proteomic responses are concordant during this adaptation remains incompletely understood.Aim. We investigated the molecular and metabolic responses of the C. neoformans H99 strain grown at 30 and 37 °C using an integrated transcriptomic, proteomic and functional approach.Methodology. RNA sequencing and quantitative proteomics were performed after 24 h of growth at 30 and 37 °C. Differentially expressed transcripts and proteins were identified, and matched transcript-protein features were analysed for directional concordance and quantitative correlation. Cellular metabolic activity was assessed using the 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assay.Results. RNA-seq analysis identified 344 upregulated and 428 downregulated transcripts at 37 °C. Upregulated transcripts were enriched in functions related to ribosome biogenesis, translation, protein folding and mitochondrial-associated processes, whereas downregulated transcripts were associated with carbohydrate metabolism and other metabolic functions. Proteomic analysis revealed a more selective response, with increased abundance of proteins associated with oxidoreductase activity, sterol and isoprenoid biosynthesis, glutamine metabolism and metal-binding functions. Integration of the transcriptomic and proteomic datasets identified 305 matched features, of which 162 (53.1%) showed directional concordance. However, no significant quantitative correlation was observed between transcript and protein fold changes (Spearman ρ = -0.005, P=0.934; Pearson r=0.003, P=0.959). Cells grown at 37 °C also showed significantly increased XTT reduction, indicating higher cellular metabolic activity under the conditions tested.Conclusion. Adaptation to host temperature involves broad transcriptional remodelling accompanied by selective proteomic changes and increased cellular metabolic activity. These findings provide a molecular framework for further investigating the mechanisms underlying thermoadaptation and their contribution to the pathogenic potential of C. neoformans.
    Keywords:  Cryptococcus neoformans; temperature adaptation; transcriptome
    DOI:  https://doi.org/10.1099/jmm.0.002205
  53. Front Epigenet Epigenom. 2026 ;4 1944086
    From chromatin to proteostasis: multilevel gene regulation in Mendelian diseases.
    Himanshu Goel, Gunjan Garg.
      Pathogenic variation can alter gene output at multiple levels, from chromatin accessibility and enhancer-promoter communication to RNA processing, translation and protein turnover. The diagnostic challenge is not to catalogue these layers, but to determine which regulatory mechanism is plausible for a given variant, phenotype, tissue and developmental context. This targeted narrative review synthesises representative Mendelian mechanisms across five linked levels: chromatin, transcription, RNA processing and stability, translation, and post-translational proteostasis. Three cross-cutting principles recur. First, distinct molecular lesions may converge on the same functional bottleneck: altered dosage, timing, localisation or disrupted protein homeostasis. Second, regulatory effects are often cell-type-, isoform-, developmental-stage- and state-specific, so assay and tissue selection are integral to interpretation. Third, a negative result in an accessible surrogate such as blood does not exclude a disease-relevant effect in brain, muscle, liver or stimulated immune cells. From these principles, the review derives a mechanism-directed diagnostic framework that links variant class to orthogonal assays, including DNA methylation profiling, chromatin and reporter assays, RNA sequencing, ribosome-level methods and protein-based studies. The framework is offered as an integrative clinical synthesis rather than a new model of gene regulation, to support variant interpretation, functional-test selection and translational prioritisation in unsolved Mendelian disease.
    Keywords:  DNA methylation; Mendelian disease; RNA splicing; episignatures; gene expression regulation; noncoding RNA; proteostasis; translational regulation
    DOI:  https://doi.org/10.3389/freae.2026.1944086
  54. Med Oncol. 2026 Oct 08. pii: 322. [Epub ahead of print]43(11):
    RBM protein family: Focusing on the occurrence, progression and treatment of cancer.
    Huhu Zhang, Wenxin Zheng, Lingxi Li, Chenhui Geng, Yuxiang Wang, Jianyu Zhang, Yulan Sun, Xuanyu Zhang, Bing Li.
      The RNA-binding motif (RBM) protein family plays a crucial role in regulating RNA metabolism, including transcription, splicing, stability, and translation. Dysregulation of RBM proteins has been increasingly implicated in the initiation, progression, and therapeutic resistance of various cancers. This review summarizes current knowledge on the RBM protein family, with a focus on their involvement in alternative splicing and m6A RNA methylation-two key post-transcriptional mechanisms that influence cancer biology. Members such as RBM5 and RBM10 function as tumor suppressors by modulating apoptosis, cell cycle, and splicing of oncogenic transcripts, while others like RBM15 and RBM15B contribute to tumorigenesis through m6A modification and downstream signaling pathways. The dual roles of certain RBM proteins in different cancer contexts highlight their complexity and potential as both biomarkers and therapeutic targets. Further investigation into the molecular mechanisms of RBM proteins may provide new insights for cancer diagnosis and treatment strategies.
    Keywords:  Alternative splicing; Biomarker; Cancer; Oncogene; RBM protein family; RNA-binding proteins; Targeted therapy; Therapeutic target; Tumor suppressor; m6A methylation
    DOI:  https://doi.org/10.1007/s12032-026-03439-8
  55. Biomol NMR Assign. 2026 Oct 09. pii: 29. [Epub ahead of print]20(1):
    1H, 13C, and 15N resonance assignments and solution structure of the first double-stranded RNA-binding domain of DExH-Box Helicase 30 (DHX30).
    Chikage Abe, Yutaka Muto, Fahu He, Mari Takahashi, Kengo Tsuda, Takashi Nagata, Akiko Tanaka, Naohiro Kobayashi, Takanori Kigawa, Peter Güntert, Mikako Shirouzu, Shigeyuki Yokoyama, Kanako Kuwasako.
      DHX30 is a member of the DExH-box helicase family and contains two double-stranded RNA-binding domains (dsRBDs) N-terminal to the helicase core domain. DHX30 plays a fundamental role in regulating the translation of transcripts encoding mitoribosomal proteins, thereby facilitating mitoribosome biogenesis. Additionally, DHX30 is involved in the formation of stress granules. These intracellular structures are composed of proteins and RNAs, including mRNAs, and form under stress conditions in association with translational repression. Recent studies have demonstrated that pathogenic mutations in DHX30 underlie a severe neurodevelopmental disorder termed neurodevelopmental disorder with variable motor and language impairment (NEDMIAL), possibly in part through aberrant stress-granule formation. Structural characterization of these RNA-binding domains is an important step toward understanding the molecular basis of DHX30 function. In this study, we focus on the first dsRBD (dsRBD-1) of human DHX30 and report its 1H, 13C, and 15N resonance assignments and solution structure. DHX30 dsRBD-1 adopts an α0-α1-α1'-β1-β2-β3-α2-α3 topology, with three additional helices (α0, α1', and α3) relative to the canonical dsRBD topology (α1-β1-β2-β3-α2). To our knowledge, this is the first experimentally determined structure of a DHX30 domain. These resonance assignments and structural insights provide a valuable foundation for future structural and functional studies of DHX30.
    Keywords:  DExH-box helicase 30 (DHX30); Mitochondrial ribosome biogenesis; NEDMIAL; dsRBD
    DOI:  https://doi.org/10.1007/s12104-026-10279-0
  56. bioRxiv. 2026 Aug 10. pii: 2026.08.08.743652. [Epub ahead of print]
    A nuclear role for the contractile protein troponin I/UNC-27 in regulating muscle aging in C. elegans.
    Allan Alcolei, Manon Froment, Laurent Molin, Charline Roy, Romain Bulteau, Jean-Louis Bessereau, Florence Solari.
      Muscle ageing is characterized by evolutionarily conserved subcellular alterations across diverse organisms. In Caenorhabditis elegans , the decline in sarcomeric gene expression is among the earliest detectable ageing-associated changes, emerging at the onset of adulthood. To identify causal regulators of muscle ageing in an unbiased manner, we developed a genetic screening strategy that enables visual monitoring of muscle ageing at both cellular and organismal scales. Using this approach, we identified a mutation that delays the age-associated loss of sarcomeric transcripts. Unexpectedly, the mutation maps to the troponin I gene unc-27 , which encodes a conserved regulator of muscle contraction not previously implicated in gene regulation. The mutation alters a single amino acid within a predicted nuclear localization signal (NLS). We found that multiple NLS motifs mediate the active transport of UNC-27 into muscle nuclei from early adulthood onward. Disruption of UNC-27 nuclear localization preserves sarcomeric gene expression during ageing and delays early hallmarks of muscle decline, including proteostatic imbalance and mitochondrial fragmentation. Transcriptomic analyses further revealed that nuclear UNC-27 selectively regulates the expression of genes encoding structural components of the muscle apparatus in adult animals. These results support the existence of a homeostatic sarcomere surveillance pathway, in which a structural protein unexpectedly acquires a transcriptional regulatory role in response to age-associated physiological state. The conservation of NLS motifs in mammalian UNC-27 orthologues suggests that this mechanism may be evolutionarily conserved, with potential relevance to human muscle physiology and disease.
    DOI:  https://doi.org/10.64898/2026.08.08.743652
  57. ACS Chem Biol. 2026 Oct 12.
    Second-Generation Acyl Modifications Stabilize RNA, Support Translation, and Suppress Cytokine Responses.
    Wenrui Zhong, Qing Sun, Linglan Fang, Sumon Pratihar, Niek N Sanders, Eric T Kool.
      Bio-reversible 2'-OH polyacylation (cloaking) has been described recently as a post-transcriptional modification strategy for stabilizing RNAs while enabling recovery of biological function after delivery into cells. Here, we probe the chemical space and utility of this method by evaluating a series of new acyl adducts for their ability to maintain protein expression levels after being substituted at high levels (ca. 25% of nucleotides) on transcripts. Reagent designs focused on the inclusion of electron-withdrawing groups near the acyl carbonyl to enhance electrophilicity. Multiple new reagents demonstrated efficient messenger RNA acylation and stabilization of the RNA against thermal cleavage for two days at 37 °C. Cellular transfection experiments with these acylated transcripts showed that certain modifications maintained native or near-native levels of translation of a protein-coding RNA, confirming the robustness of the approach across a broad set of chemotypes. We further report that protein-coding RNAs polyacylated with selected reversible acyl groups show transiently reduced proinflammatory cytokine responses relative to unmodified RNA. Together, these findings expand the functional boundaries of bio-reversible 2'-OH acylation and provide guidance for future development of RNA protection and modification strategies.
    DOI:  https://doi.org/10.1021/acschembio.6c00657
  58. Redox Biol. 2026 Oct 03. pii: S2213-2317(26)00422-2. [Epub ahead of print]97 104423
    Tyrosine nitration: An emerging mechanistic landscape in neurodegeneration and cardiopulmonary disease.
    Nirbachita Adrita, Inge Claassen, Miranda Huerta, Stephen M Black, Alvaro G Estevez, Blaine R Roberts, Joseph S Beckman, Maria Clara Franco.
      Protein tyrosine nitration is a post-translational modification associated with conditions of oxidative and inflammatory stress, driven by the production of reactive oxygen and nitrogen species (ROS and RNS). Once considered primarily a footprint of oxidative damage, tyrosine nitration is increasingly recognized as a selective modification that, in specific biological contexts, can alter protein structure, stability, enzymatic activity, and interaction networks. Mechanistically, nitration occurs through peroxynitrite-dependent and heme-peroxidase-dependent pathways and preferentially targets specific tyrosine residues based on local protein structure, solvent accessibility, and microenvironmental chemistry. Accumulating evidence has identified disease-specific nitration signatures across multiple pathological contexts. In neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, nitration of proteins such as tau, α-synuclein, manganese superoxide dismutase, ATP synthase, glyceraldehyde-3-phosphate dehydrogenase, heat shock proteins, and cytoskeletal components contributes to mitochondrial dysfunction, protein aggregation, metabolic failure, and neuronal loss. Similarly, in cardiovascular and pulmonary diseases, protein tyrosine nitration disrupts vascular and epithelial homeostasis by impairing endothelial signaling, fibrinolysis, lipid metabolism, and barrier integrity through modification of key regulatory proteins. By influencing phosphorylation-dependent signaling, enzymatic function, and protein-protein interactions, tyrosine nitration contributes to the connection between redox imbalance and progressive cellular and tissue dysfunction. This review summarizes current mechanistic insights into site-specific protein tyrosine nitration, highlights the emerging disease-associated nitroproteome, and discusses how advances in analytical and structural approaches are redefining nitration as a functional regulatory modification. Understanding the molecular determinants and consequences of tyrosine nitration may enable the development of targeted diagnostics and therapeutic strategies across diverse human diseases.
    Keywords:  Cardiovascular disease; Neurodegeneration; Peroxynitrite; Pulmonary disease; Reactive nitrogen species; Tyrosine nitration
    DOI:  https://doi.org/10.1016/j.redox.2026.104423
  59. bioRxiv. 2026 Aug 16. pii: 2025.09.02.673827. [Epub ahead of print]
    Mechanistic insights into RAN translation within the Huntingtin coding sequence.
    Amy Krans, Richard M Albertson, Connor J Maltby, Peter K Todd.
      Nucleotide repeat expansions support production of toxic peptides from putatively non-coding regions of the human genome without use of an AUG initiation codon. This process, known as RAN translation, was originally described at CAG repeats with products generated in all three possible reading frames. Recently, cryptic mis-splicing of mRNAs in which the CAG repeat acts as a splice acceptor was proposed as an alternative mechanism for RAN protein production. To investigate this, we generated DNA and RNA based reporters to assess RAN translation in the context of a CAG repeat expansion in exon 1 of the Huntingtin gene ( HTT), associated with Huntington Disease. HTT CAG repeats support RAN translation in both the alanine (GCA) and glutamine (CAG) frames, with or without upstream AUG start codons or near-AUG cognate codons, and at levels comparable to RAN translation from CGG and GGGGCC repeats. CAG RAN translation products were readily detectable from in vitro transcribed RNAs transfected into human cells and rodent neurons - suggesting that plasmid based aberrant splicing into CAG repeats cannot fully explain the observed phenomena. These findings indicate that RAN translation from HTT CAG repeats shares key mechanistic parameters with other disease-associated repeat expansions.
    Key Points: Translation at HTT CAG repeats occurs in at least two reading frames absent any AUG start codon.Like RAN translation at other repeats, HTT CAG RAN translation is enhanced by cell stress.HTT CAG RAN translation readily occurs from in vitro transcribed RNAs in neurons.
    DOI:  https://doi.org/10.1101/2025.09.02.673827
  60. Mol Biol Rep. 2026 Oct 07. pii: 1675. [Epub ahead of print]53(1):
    Mitochondrial dysfunction of renal tubular epithelial cells in chronic kidney disease-associated fibrosis: from organelle homeostasis to multicellular remodeling.
    Shaodan Ni, Zhipeng Li, Xiaolin Pan, Yijia Zhang, Xiaoli Nie.
      Chronic kidney disease (CKD) is a major global health burden, and renal fibrosis is a common pathological correlate of progressive loss of kidney function. Renal tubular epithelial cells (RTECs), particularly proximal tubular epithelial cells (PTECs), contain abundant mitochondria and depend on oxidative metabolism to support solute transport. This metabolic specialization renders them vulnerable to hypoxia, lipotoxicity, uremic toxins, aging, inflammation, and hemodynamic stress. Persistent mitochondrial injury can suppress fatty acid oxidation and oxidative phosphorylation, deplete nicotinamide adenine dinucleotide, increase mitochondrial reactive oxygen species, destabilize mitochondrial DNA, and disrupt biogenesis, dynamics, mitochondria-associated membrane signaling, and mitophagy. These abnormalities promote maladaptive repair, senescence, inflammatory cell death, and paracrine signaling to fibroblasts, macrophages, endothelial cells, and pericytes. Evidence is organized within a tubule-to-niche framework that distinguishes causal perturbation from temporal or transcriptomic association, model-specific findings from cross-model convergence, and experimental efficacy from clinical translation. Single-cell, spatial, and organoid studies are considered alongside evidence from human biopsy specimens and biomarkers. Mitochondrial dysfunction is thus treated as a context-dependent contributor to, and amplifier of, CKD-associated fibrotic remodeling rather than a universal initiating event. Although strategies targeting bioenergetics, redox balance, mitochondrial quality control, and tubular delivery are promising, translation is constrained by disease heterogeneity, intervention timing, target specificity, pharmacokinetics, and the scarcity of validated human antifibrotic endpoints.
    Keywords:  Chronic kidney disease; Mitochondrial dysfunction; Multicellular remodeling; Organelle homeostasis; Renal fibrosis; Renal tubular epithelial cells
    DOI:  https://doi.org/10.1007/s11033-026-12861-0
  61. Proc Natl Acad Sci U S A. 2026 Oct 13. 123(41): e2610192123
    Chemoreceptor complexes signal through a protein-ordering and stabilization mechanism.
    Jessica J Allen, Edward A Esposito, Isabella J Jankowski, Katherine W Lu-Diaz, Lynmarie K Thompson.
      Membrane protein complexes are critical to many cellular processes and have proven to be good targets for a variety of therapeutics. One such complex is the bacterial chemoreceptor signaling complex, which has potential as a target for novel antibiotics. This complex is responsible for sensing chemical signals in the environment to bias swimming of the bacterial cell toward more favorable conditions. While these complexes are well studied, the mechanisms of signal transduction and kinase control are still not fully understood. We have applied multiple thermal stability measurements and limited proteolysis to gain insight into how complex formation and signaling state change the thermal stability and structural properties of the proteins and complexes. We show that the activated signaling complexes are more strongly associated, ordered, and thermally stable than the inactive complexes. This direct evidence that both the chemoreceptor and the kinase are significantly stabilized by assembly into kinase-active complexes is consistent with our previous hydrogen deuterium exchange mass spectrometry results and our proposed order-induced activation model. We propose that signaling inputs modulate the structural order and stability of the partially disordered cytoplasmic domain, which in turn modulates the stability of the catalytic domain of the kinase, such that ordering of the cytoplasmic domain stabilizes and activates the kinase.
    Keywords:  chemotaxis; protein disorder; signal transduction; thermal stability
    DOI:  https://doi.org/10.1073/pnas.2610192123
  62. Signal Transduct Target Ther. 2026 Oct 06. pii: 425. [Epub ahead of print]11(1):
    Glutamine metabolism in health and disease.
    Junsheng Zhao, Yajie Lin, Rong Gao, Hainv Gao, Lanjuan Li.
      Glutamine is the most abundant free amino acid in the body. It plays a central role in cellular metabolism, connecting synthetic and catabolic pathways, and maintaining life activities under physiological and pathological conditions. This review systematically explores the dual role of glutamine metabolism in health and disease. Glutamine is not only the main energy and nitrogen source for rapidly proliferating cells, such as immune cells, intestinal epithelial cells, and cancer cells but also participates in several key biological processes, such as nucleotide synthesis, REDOX balance, and immune regulation. Glutamine metabolism is often abnormally activated or disrupted in disease states, such as "glutamine addiction" in cancer and excitotoxicity and mitochondrial dysfunction in neurodegenerative diseases. Disorders of glutamine metabolism are also present in metabolic diseases (such as diabetes and MAFLD) and cardiovascular diseases. In addition, gut microbes regulate host glutamine metabolism through metabolites and signaling pathways, further affecting the disease process. Therapeutic strategies to target glutamine metabolism include inhibition of key enzymes or transporters, as well as exogenous glutamine supplementation. However, the effects of these strategies are context-dependent and need to be applied individually according to the specific pathological status of patients. Future research should focus on tissue-specific metabolic profiling, integrated multiomics analysis, and the development of combined treatment strategies to fully realize the potential of glutamine metabolism in disease treatment.
    DOI:  https://doi.org/10.1038/s41392-026-02981-1
  63. bioRxiv. 2026 Aug 10. pii: 2026.08.09.743795. [Epub ahead of print]
    A Quantitative Two-Channel Genetic Reporter for Selenocysteine Biosynthesis and Incorporation.
    Andrew Gilmour, Qiyao Wei, Jessica Hellinger, Devon L Kulhanek, Zach Jansen, Katelyn M Baumer, Jennifer S Brodbelt, Ross Thyer.
      Selenocysteine (Sec), the 21 st amino acid, is a rare non-canonical amino acid that represents an attractive target for protein engineering due to its desirable chemical properties such as high affinity for metals, strong nucleophilicity, and reversible covalent bond formation. To bypass the natural constraints on Sec placement within proteins, several strategies have been developed to rewire the native translational machinery to enable site-specific incorporation. However, these usually abolish the quality control mechanism that excludes the serine-charged selenocysteinyl-tRNA (Ser-tRNA Sec ), the immediate biosynthetic precursor, from translation resulting in heterogenous protein species. This challenge is confounded by a lack of genetic tools to accurately report the selenylation state of the tRNA pool as most are blind to competing process of Ser incorporation, which can only be observed using analytical methods. To resolve this issue, we have developed a new fluorescent reporter, Se lenocysteine A djusted R atiometric Ch romophore (SeARCh), which exhibits two distinct spectral outputs dependent on the incorporation of either Ser (red) or Sec (green). Using SeARCh, we define several factors which influence the observed Sec:Ser ratio and construct a new hybrid biosynthetic pathway with improved performance, achieving 90% Sec incorporation. Furthermore, SeARCh displays unusually complex mass spectra due to the isotope distribution of selenium and heterogenous nature of the protein in solution and we report specific methods to account for this behaviour and precisely quantify the rare Ser-containing species found at high Sec incorporation efficiencies. Our findings suggest that the equilibrium between selenoprotein and tRNA Sec expression levels is a key driver of incorporation efficiency and implies a process that is broadly biosynthetically constrained. Collectively these tools represent a significant advance in the metrology of selenocysteine biosynthesis and incorporation and can be used to inform and standardize future engineering efforts.
    DOI:  https://doi.org/10.64898/2026.08.09.743795
This page is being maintained by Thomas Krichel. It was last updated on 2026‒10‒11 at 5:44.