bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–05–10
fifty-one papers selected by
Cédric Chaveroux, CNRS
  1. The tRNA dihydrouridine synthase DusA has a distinct mechanism in optimizing tRNAs for translation.
  2. Ribonucleobase Oxidation and Ribonucleases Involved in the Degradation of Oxidized RNA.
  3. An integrated RNA-centric imaging and omics approach reveals distinct properties and composition of neuronal RNA granules.
  4. RNA methylation in urological cancers: regulatory logic, biological functions, and clinical relevance.
  5. Increased Protein Synthesis With Reduced Endoplasmic Reticulum Stress Defines a Specific Adaptation in Pancreatic Acinar Metaplasia.
  6. Suppression of upstream ORF translation is not a widespread mechanism of translational stimulation by yeast helicase Ded1.
  7. Dysregulated selective translation in cancer: The pivotal functions of RNA-binding proteins and emerging therapeutic avenues.
  8. Ribosomal RNA methylation by GidB modulates discrimination of mischarged tRNA.
  9. Ribosome biogenesis bottlenecks reveal vulnerabilities in cancer.
  10. A molecular stabiliser of an inhibitory eIF2B-eIF2(αP) complex activates the Integrated Stress Response.
  11. N-terminal formylmethionine as a degron and a specific signal in proteostasis and stress adaptation.
  12. RNA methylation in cardiovascular remodeling: Molecular mechanisms, biomarkers, and therapeutic strategies.
  13. The different roles of the eS31 ribosomal protein in ribosome biogenesis and translation in Saccharomyces cerevisiae.
  14. Pyroptosis regulated by m6A modification: implications for pyroptosis-related disease therapy.
  15. CDS-localized m6A drives co-translational RNA decay to relieve biotic and abiotic endoplasmic reticulum stresses.
  16. Stress-induced breakup: tRNA-derived small RNAs in biology.
  17. ISRIB as a Prototype eIF2B Activator: Pharmacology, Mechanisms, and Translational Potential in Aging-Related Cognitive Disorders.
  18. Protein synthesis during mouse spermatogenesis.
  19. Phase separation of TRNAU1AP protein sustains selenoprotein translation and promotes glioblastoma tumorigenesis.
  20. Enhancing mRNA stability and translational potential through tailored modifications at the 3' end.
  21. Structural and biochemical characterization of yeast Tcd enzymes installing the post-transcriptional modification ct6A in tRNA.
  22. The Expanding Landscape of ADP-Ribosylation: Protein, DNA, RNA, and Mitochondrial Regulation.
  23. The role of protein prenylation in kidney diseases: Molecular basis and therapeutic implications.
  24. The epitranscriptomic m6A RNA modification modulates the synapse in ageing and in a mouse model of synucleinopathy.
  25. Yield and fidelity of early steps of ribosome-free translation depend on the RNA anchoring.
  26. ZBP1's Inability to Convert Unmodified RNAs to the Z-form Underlies a Balanced Mechanism of RNA Recognition with ADAR1.
  27. Evaluating Malat1-derived 3'end sequences for functional transgene expression in human cells using synthetic mRNA delivery.
  28. Therapy as a State-Generator: Dynamic Phenotypic Landscapes and Adaptive Stress Circuits in Chemotherapy Resistance of Breast Cancer.
  29. The dynamics and strategy of RNA replication in astroviruses.
  30. The deletion of HSP60 in cholinergic neurons alleviates LPS-induced depressive-like behaviours in mice by reducing neuroinflammation.
  31. Unveiling the adaptive structure-function synergy in thermophilic translation initiation factor 1: A molecular dynamics framework.
  32. Architectural principles of the ribosomal large subunit revealed by A-helix spatial organization.
  33. Giant viruses: Bringing your own translation machinery makes infection less stressful.
  34. CELF family of RNA-binding proteins: roles in disease biology and potential for therapeutic intervention.
  35. Mechanism of nucleolytic degradation of human ribosomes.
  36. Multifaceted regulatory role of proline‑ and glutamine-rich splicing factor in tumors (Review).
  37. Structure-Encoded Oxidation Enables Nucleotide-Resolved RNA Editing, Conjugation, and Structural Probing.
  38. Translational hub ribosomal protein S5 promotes glioblastoma progression by affecting translation patterns.
  39. A Caenorhabditis elegans spatiotemporal proximity atlas reveals the MAPK p38 as a generator of phenotypic plasticity in vivo.
  40. AAA+ protein unfoldases-the Moirai of the proteome.
  41. Mettl5 coordinates protein production and degradation of PERIOD to regulate sleep in Drosophila.
  42. Cigarette Smoke Induces Canonical Stress Granule Formation in Human Bronchial Epithelial Cells in Reactive Oxygen Species- and PERK-Dependent Manners.
  43. An intricate functional relationship between NuA4 and Sfp1 regulates ribosome biogenesis in response to nutrient availability.
  44. Thermospermine drives dual-action ribosomes to shape plant xylem development.
  45. RNAStructuromeDB: a transcriptome-wide database of predicted RNA secondary structures with integrated APIs for functional annotation and RNA-targeted drug discovery.
  46. A microRNA generated via lysosomal processing of ribosomal RNA suppresses proinflammatory responses.
  47. Salubrinal-activated integrated stress response protects against doxorubicin-induced cardiotoxicity via activating transcription factor 4-mediated antioxidant defense and glutathione homeostasis.
  48. Functional Analysis of MADS-Box Gene Family in Stress Response and Prospects of Breeding Application.
  49. Polyamine Metabolism and the DHPS/eIF5A Hypusination Axis: From Metabolic Reprogramming to a Therapeutic Achilles' Heel in Melanoma.
  50. Rational construction of rpsL or/and rpoB merodiploids affects biosynthesis of secondary metabolite in Streptomyces.
  51. Stress Granule Sequestration of CCR4-NOT Promotes Poly(A) Lengthening of Stress-Survival Transcripts.
  1. Nucleic Acids Res. 2026 Apr 23. pii: gkag432. [Epub ahead of print]54(8):
    The tRNA dihydrouridine synthase DusA has a distinct mechanism in optimizing tRNAs for translation.
    Sarah K Schultz, Nadia Hossain, Lauren Barnes, Tirathjot Kaur, Kristin S Koutmou, Ute Kothe.
      Dihydrouridine (D) is one of the most highly conserved RNA modifications across all domains of life. D20 within the tRNA D loop is particularly conserved and is formed by DusA in Escherichia coli. However, the mechanisms and cellular functions of DusA and D20 remain poorly understood. Here, we characterize DusA's role in tRNA binding, cofactor oxidation, and modification activity, along with its impact on tRNA maturation and translation. We find that DusA binds tRNA via a two-step mechanism involving a local structural rearrangement and exhibits a higher affinity for previously modified tRNA compared to unmodified tRNA. Unlike the T arm modifying enzymes TrmA and TruB, DusA does not broadly increase cellular aminoacylation for all tRNAs but enhances the charging of specific tRNA species. Despite limited alterations in overall tRNA charging and abundance in cells lacking DusA, DusA selectively improves translation at several specific codons, potentially indicating a direct contribution for dihydrouridine to the function of certain tRNAs on the ribosome. In conclusion, our findings suggest DusA acts nonredundantly with and complementary to TrmA and TruB in fine-tuning protein synthesis.
    DOI:  https://doi.org/10.1093/nar/gkag432
  2. Biomolecules. 2026 Apr 10. pii: 564. [Epub ahead of print]16(4):
    Ribonucleobase Oxidation and Ribonucleases Involved in the Degradation of Oxidized RNA.
    Dagoberto Grijalva-Flores, Marino J E Resendiz.
      Oxidation of RNA has gained interest from the community due, in part, to a link in the progression/development of disease as well as other biological processes such as apoptosis, ageing, hibernation, and signalling, amongst others. Different types of RNA with varying functions and size have been shown to be oxidized in vivo, including ribosomal RNA (rRNA), transfer RNA (tRNA), microRNA (miRNA), messenger RNA (mRNA), and mitochondrial RNA (mtRNA). This process occurs from reactions between reactive oxygen species (ROS) and all biopolymers, including RNA, from endogenous as well as exogenous sources. As a consequence, mechanisms that handle oxidized RNA are important, and enzymatic degradation is the most commonly studied process to date. This review focuses on the ribonucleases that have been shown to play a role in the degradation of oxidized RNA. While emphasis is placed on, arguably, the most common oxidatively generated chemical modification, 8-oxo-7,8-dihydroguanosine (8-oxoG), the products that arise from the oxidation of other canonical nucleosides as well as naturally occurring modifications are also discussed in the context of RNA oxidation. Processing of oxidized RNA via its enzymatic degradation is likely the main route, but a potential role of other proteins involved in the handling of oxidized RNA is hypothesized, e.g., helicases, export proteins, and extracellular environments. We postulate that this is an area with great potential for discovery.
    Keywords:  RNA 8-oxoG; RNA oxidation; oxidized RNA degradation; oxidized RNA protein binding; ribonucleobase oxidation
    DOI:  https://doi.org/10.3390/biom16040564
  3. bioRxiv. 2026 Apr 30. pii: 2026.04.27.721160. [Epub ahead of print]
    An integrated RNA-centric imaging and omics approach reveals distinct properties and composition of neuronal RNA granules.
    Jackson A Rogow, Ella Doron-Mandel, Ronald Cutler, Leti Núñez, Ricardo Vazquez, Laura Harris, Marko Jovanovic, Robert H Singer, Sulagna Das.
      RNA granules are essential regulators of post-transcriptional gene expression, enabling mRNA transport, localization, and local translation in neurons. The localized transcriptome is diverse; however, how different mRNAs are organized into granules for efficient localization and translation remains unknown. Here, we combine real-time endogenous single RNA imaging with protein and RNA proximity labeling to investigate two distinct endogenous neuronal mRNA granule populations, Actb and Arc , in stimulated primary hippocampal neurons. Using orthogonal RNA labeling systems in a dual knock-in mouse model, we show that Actb and Arc mRNAs are packaged into spatially segregated granules with distinct trafficking dynamics, localization kinetics, and responses to synaptic stimulation. Actb granules displayed rapid and sustained localization, whereas Arc granules showed delayed, transient recruitment, consistent with their respective roles in structural and activity-dependent plasticity. Proximity labeling reveals that these granules are distinct in their mRNA composition, despite sharing core RNA-binding proteins, suggesting that shared cis-regulatory elements within mRNA 3'UTR regions drive selective co-packaging of mRNAs into unique granules. Together, these findings demonstrate that neuronal mRNAs are differentially sorted into molecularly and functionally distinct granules, providing a framework for understanding how precise spatio-temporal control of mRNA localization and translation is achieved across complex neuronal arbors.
    DOI:  https://doi.org/10.64898/2026.04.27.721160
  4. Front Immunol. 2026 ;17 1790638
    RNA methylation in urological cancers: regulatory logic, biological functions, and clinical relevance.
    Jiahao Peng, Chong Xie, Zhangmin Xie, Feng Tang, Zhiying Wang, Minhao Liu, Li Yu, Chenhao Tang, Ziyang Liu, Zuowei Yuan, Longwei Liao, Xinpan Zou, Xuran Liu, Mingyang Yi, Huangheng Tao, Wei Wei, Tao Liu, Yixiang Liao.
      Urological malignancies, including prostate, bladder, and renal cancers, remain a major clinical challenge because of tumor heterogeneity, disease progression, and therapeutic resistance. In this context, RNA methylation has emerged as an important post-transcriptional regulatory layer in cancer biology. Importantly, the biological consequences of RNA methylation are not dictated by chemical modifications alone, but by coordinated networks of regulatory proteins that install, remove, and interpret these marks, thereby shaping RNA fate and gene expression programs. Among currently studied RNA modifications, N6-methyladenosine (m6A) provides the most mature mechanistic framework, whereas non-m6A regulators remain comparatively less well characterized. In this review, we systematically summarize the regulatory logic underlying RNA methylation-mediated control in urological cancers, with particular emphasis on how distinct classes of regulatory proteins influence RNA stability, translation, metabolism, and other post-transcriptional processes. We further integrate current evidence across multiple RNA methylation types, including m6A, 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G), while highlighting the relative immaturity of non-m6A evidence in these malignancies. We also provide an overview of current m6A detection technologies and discuss their methodological strengths, limitations, and appropriate research applications. Beyond mechanistic insights, we discuss the emerging clinical relevance of RNA methylation regulators in urological malignancies, particularly in relation to diagnostic-related evidence, prognostic stratification, immune-related relevance, and treatment-associated adaptation. In addition, we summarize current therapeutic efforts targeting RNA methylation pathways, including small-molecule inhibitors and related translational strategies, while emphasizing their present limitations. Overall, current evidence supports RNA methylation as a biologically important and increasingly translationally relevant framework in urological cancers, but not yet as a clinically mature one.
    Keywords:  N1-methyladenosine (m1A); N6-methylAdenosine (m6A); N7-methylguanosine (m7G); RNA methylation; RNA modification; bladder cancer (BCa); prostate cancer (PCa); renal cell carcinoma (RCC)
    DOI:  https://doi.org/10.3389/fimmu.2026.1790638
  5. Gastro Hep Adv. 2026 ;5(6): 100931
    Increased Protein Synthesis With Reduced Endoplasmic Reticulum Stress Defines a Specific Adaptation in Pancreatic Acinar Metaplasia.
    Maxime Libert, Sophie Quiquempoix, Leyre López-Muneta, Ludivine Wacheul, Sabine Cordi, Christiane Zorbas, Patrick Jacquemin.
       Background and Aims: Tumorigenesis is usually associated with increased protein synthesis rates coupled with increased endoplasmic reticulum (ER) stress. In the pancreas, acinar cells already exhibit a very high protein synthesis rate in normal physiological conditions, which raises the question of how this cell type adapts during pancreatic tumor formation. Here, we characterize how acinar cells modulate their protein synthesis rate in metaplastic lesions, which are precursor lesions of pancreatic ductal adenocarcinoma.
    Methods: We evaluated protein synthesis by puromycin incorporation assays and investigated the control of translation and ER stress by transcriptomic analyses and phenotyping of a mouse model of pancreatic ductal adenocarcinoma. We also assessed the level of ribosomal RNA methylation systematically using a deep sequencing-based technique, RiboMethSeq.
    Results: During pancreatic tumorigenesis, protein synthesis rates were significantly increased in acinar-to-ductal metaplasia compared with normal acinar cells. This was associated with enhanced expression and activity of translation initiation factors, and with increased production of ribosomal components and ribosome assembly factors. We detected differential ribosomal RNA methylation at conserved ribosomal positions near the peptidyl transferase center and the exit tunnel, suggesting a potential role in modulating translation and/or cotranslational protein folding. Despite increased protein synthesis, ER stress was reduced, which was associated with an overall reduction in N-linked glycosylation and increased expression of proteasome components.
    Conclusion: Our findings reveal a pancreas-specific adaptation of the translational machinery during tumorigenesis, characterized by the production of differentially modified ribosomes and a combination of increased protein synthesis rate and decreased ER stress. This highlights the diversity of adaptive protein synthesis in transforming tissues.
    Keywords:  ER Stress; Pancreatic Tumorigenesis; Ribosome; Translation Initiation
    DOI:  https://doi.org/10.1016/j.gastha.2026.100931
  6. Nucleic Acids Res. 2026 May 05. pii: gkag427. [Epub ahead of print]54(9):
    Suppression of upstream ORF translation is not a widespread mechanism of translational stimulation by yeast helicase Ded1.
    Rakesh Kumar, Gemma May, Neelam Dabas Sen, C Joel McManus, Alan G Hinnebusch.
      Ded1 is an essential DEAD-box helicase in yeast that broadly stimulates translation initiation and is critical for messenger RNAs (mRNAs) with structured 5' untranslated regions (UTRs). We have evaluated the proposal that Ded1 stimulates translation primarily by preventing initiation at upstream open-reading-frames (uORFs) associated with stable secondary structures. By Ribo-seq analysis under experimental conditions designed to suppress artifactual 5'UTR translation, we found that reduced translation of the main open-reading-frames (mORFs) in native mRNAs is generally not accompanied by increased 5'UTR translation in ded1 mutant cells, and that the presence of translated uORFs in yeast mRNAs generally does not confer heightened dependence on Ded1 for efficient translation of mORFs. Results from a high-throughput reporter assay examining native 5'UTRs reinforce the importance of Ded1 in initiation from structured 5' UTRs and show that impairing Ded1 has minimal effects on translational repression by uORFs. Our results demonstrate that, in cells growing vegetatively in rich medium, translational stimulation by suppression of inhibitory uORFs is restricted to a minority of Ded1 targets, and that unwinding of 5' UTR secondary structures per se is the principal mechanism for Ded1 stimulation of translation initiation.
    DOI:  https://doi.org/10.1093/nar/gkag427
  7. Biochim Biophys Acta Rev Cancer. 2026 May 05. pii: S0304-419X(26)00074-0. [Epub ahead of print] 189602
    Dysregulated selective translation in cancer: The pivotal functions of RNA-binding proteins and emerging therapeutic avenues.
    Xiao Hu, Jiayan Xie, Yaping Li, Ke Li, Bin Wang.
      mRNA translation represents an essential layer of gene expression regulation, enabling rapid adaptation to external stimuli and maintenance of cellular homeostasis. Dysregulation of this process is a hallmark of cancer, exploited by malignant cells through alterations in trans-acting factors and cis-regulatory elements to rewire mRNA translation. This reprogramming preferentially translates oncoproteins over tumor-suppressors, ultimately driving tumorigenesis. Although RNA-binding proteins (RBPs) are key trans-regulators involved in almost all steps of mRNA translation, their specific roles in dictating dysregulated translation selectivity in cancer remain to be fully elucidated. Herein, we describe the multi-layered regulation of selective translation by RBPs, which are hijacked by malignant cells to decode the molecular grammars embedded in transcripts, including specific RNA structures, cis-regulatory sequence elements, and epitranscriptomic modifications. Moreover, we comprehensively summarize the pivotal role of RBP-mediated selective translation in shaping multiple malignant behaviors of cancer cells, thereby broadening our understanding of translational control during cancer progression. Therapeutically, we highlight emerging strategies to intervene in these RBP-driven reprogramming of translational circuits, providing an innovative direction for future anti-cancer therapeutics.
    Keywords:  Molecular targeted therapy; RNA-binding proteins; Selective translation; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189602
  8. bioRxiv. 2026 Apr 23. pii: 2021.03.02.433644. [Epub ahead of print]
    Ribosomal RNA methylation by GidB modulates discrimination of mischarged tRNA.
    Zhuo Bi, Yu-Xiang Chen, Iris D Young, Mohamad T Dandan, Hemant Joshi, Hong-Wei Su, Yuemeng Chen, Jia-Yao Hong, James S Fraser, Babak Javid.
      Despite redundant cellular pathways to minimize translational errors, errors in protein synthesis are common. Pathways and mechanisms to minimize errors are classified as pre-ribosomal or ribosomal. Pre-ribosomal pathways are primarily concerned with the appropriate charging of tRNAs with their cognate amino acid. By contrast, the ribosomal decoding centre is considered 'blind' to mischarged tRNAs since these have cognate codon•anti-codon pairing. Here, we identified that in mycobacteria, deletion of the 16S ribosomal RNA methyltransferase gidB led to increased ribosomal discrimination of mischarged tRNAs. Discrimination only occurred in mycobacteria enriched from environments or genetic backgrounds with high rates of mistranslation. GidB deletion was necessary but not sufficient for reducing mistranslation due to misacylation. Analysis of new cryoEM structures of the M. smegmatis ribosomes derived from wild-type and gidB -deleted strains point to the interaction between the base methylated by GidB on the 16S RNA and an asparagine on the ribosomal S12 protein that when mistranslated to aspartate may be involved in altering translational fidelity. Our data suggest a mechanism by which mycobacterial ribosomes can discriminate mischarged tRNAs and that 16S rRNA differential methylation by GidB may act to prevent catastrophic translational error.
    DOI:  https://doi.org/10.1101/2021.03.02.433644
  9. bioRxiv. 2026 Apr 21. pii: 2026.04.20.719509. [Epub ahead of print]
    Ribosome biogenesis bottlenecks reveal vulnerabilities in cancer.
    Lifei Jiang, Qiwei Yu, Sofia A Quinodoz, Jordy F Botello, Sabreen Alam, Jing Xia, Jonida Trako, Troy J Comi, Aya A Abu-Alfa, Yong Wei, Andrej Košmrlj, Yibin Kang, Clifford P Brangwynne.
      Cell growth requires elevated protein synthesis, which depends on the production of ribosomes. Ribosome biogenesis is a complex, multi-step pathway in which newly transcribed precursor ribosomal RNA (rRNA) undergoes coordinated processing and assembly in the nucleolus to produce the small and large ribosomal subunits (SSU and LSU). 1-3 Oncogene activation stimulates rRNA transcription and processing, giving rise to enlarged nucleoli that produce thousands of ribosomes every minute. 4,5 However, efficient ribosome production requires tight coordination across numerous maturation steps, and it remains unclear if elevated rDNA transcription is proportionally converted into mature ribosomes, or whether imperfect coordination constrains the output yield. Here, we quantify pre-rRNA transcription (input) and compare it with newly-assembled cytoplasmic ribosomes (output), revealing that oncogene activation reduces the efficiency of ribosome production. Using a quantitative pulse-chase sequencing approach with mathematical modeling to resolve rRNA maturation kinetics, we found that oncogene activation creates late-stage processing bottlenecks, characterized by delayed precursor maturation and increased degradation. Perturbation of late-stage ribosome biogenesis factors preferentially impaired oncogene-driven cell growth, and limited tumor growth in mouse models, suggesting that these bottlenecks represent selective vulnerabilities in cancer, created by imbalanced biosynthetic flux. Together, these findings reveal that oncogene-driven ribosome production is imperfectly coordinated across maturation steps, and suggest that capacity limits in multi-step assembly pathways may be therapeutically exploitable in cancer and other diseases.
    DOI:  https://doi.org/10.64898/2026.04.20.719509
  10. Nat Commun. 2026 May 06.
    A molecular stabiliser of an inhibitory eIF2B-eIF2(αP) complex activates the Integrated Stress Response.
    Fiona Shilliday, Miguel Gancedo-Rodrigo, Ginto George, Shintaro Aibara, Santosh Adhikari, Syedah Neha Ashraf, Evelyne J Barrey, Paolo A Centrella, Damian Crowther, Paige Dickson, Diana Gikunju, Marie-Aude Guié, John P Guilinger, Anders Gunnarsson, Heather P Harding, Christopher D Hupp, Rachael Jetson, Anthony D Keefe, JeeSoo Monica Kim, Richard J Lewis, Taiana Maia de Oliveira, Jennifer Le-Marshall, Usha Narayanan, Katherine A Nugai, Dušan Petrović, Emma Rivers, David Ron, Daisy Stringfellow, Karl Syson, Lewis Ward, John T S Yeoman, Yan Yu, Ying Zhang, Alisa Zyryanova, David J Baker, Perla Breccia, John E Linley.
      Eukaryotic initiation factor 2B (eIF2B), a guanine nucleotide exchange factor (GEF), promotes protein synthesis by charging translation initiation factor 2 (eIF2) with GTP. Stress-induced phosphorylation of eIF2 on its α-subunit [eIF2(αP)] inhibits this reaction triggering a protective Integrated Stress Response (ISR). A DNA-encoded chemical library (DEL) screen for modulators of eIF2B, led to the identification of a chemical series that stabilises the inactive state of eIF2B, stimulating the ISR. Cryo-EM of compound-bound eIF2B reveals a conformational switch to the inactive state engaged by eIF2(αP). In cells, compound activity is sensitive to eIF2's phosphorylation state and to a competing eIF2B ligand (ISRIB) that activates the GEF allosterically. These findings establish the feasibility of targeting eIF2B with a drug-like allosteric inhibitor, that serves as an ISR activator (ISRAC), paving the way to explore the therapeutic potential of eIF2B-directed ISR activation.
    DOI:  https://doi.org/10.1038/s41467-026-72688-y
  11. Exp Mol Med. 2026 May 08.
    N-terminal formylmethionine as a degron and a specific signal in proteostasis and stress adaptation.
    Chang-Seok Lee, Dasom Kim, Cheol-Sang Hwang.
      N-terminal (Nt) methionine formylation, once thought restricted to bacteria and organelles, is now recognized as a stress-inducible initiator modification in the eukaryotic cytosol. Under metabolic or environmental stress, mitochondrial methionyl-transfer RNA (tRNA) formyltransferase mislocalizes to the cytosol, generating formylated initiator tRNA (fMet-tRNAi) that initiates translation with N-formylmethionine (fMet). Nascent chains bearing Nt-fMet activate an fMet-directed ribosome-associated quality control checkpoint early in elongation, recruiting ribosome-splitting and disaggregation factors. Stalled complexes are routed to stress granules, conserving mRNA, translation machinery, and energy, while limiting aggregation. During prolonged stress, newly synthesized fMet proteins undergo maturation or selective degradation via the fMet/N-degron pathway. In mammals, E3 ligase TRIM52 acts as an Nt-fMet recognin, modulating apoptosis. Proteolytic clearance of cytosolic fMet substrates releases formylated peptides and free fMet, which are elevated in critical illness and activate formyl peptide receptors - linking translation surveillance to innate immune and inflammatory signaling in sepsis and age-related disease. Advances in N-terminomics and anti-fMet reagents now allow direct detection and quantification of cytosolic fMet proteoforms. This Review integrates bacterial and organellar paradigms with emerging cytosolic mechanisms, examines regulatory gating of Nt-formylation, and highlights therapeutic strategies to restore proteostasis and counter fMet-associated pathology.
    DOI:  https://doi.org/10.1038/s12276-026-01723-1
  12. Mol Biol Rep. 2026 May 05. pii: 717. [Epub ahead of print]53(1):
    RNA methylation in cardiovascular remodeling: Molecular mechanisms, biomarkers, and therapeutic strategies.
    Huilin Li, Qiming Fan, Jiajun Sang, Chengxia Kan, Xiaodong Sun, Kexin Zhang.
      N6-methyladenosine (m6A) and 5-methylcytosine (m5C) are dynamic and reversible RNA modifications that play important roles in cardiovascular diseases (CVDs). By regulating RNA stability, splicing, transport, translation, and degradation, m6A and m5C shape key pathological processes including endothelial dysfunction, inflammation, apoptosis, fibrosis, impaired contractility, and metabolic remodeling. Core regulators, including METTL3, METTL14, fat mass and obesity-associated protein (FTO), AlkB homolog 5 (ALKBH5), and YTH family proteins for m6A, as well as NSUN2, DNMT2, TET2, and ALYREF YBX1 for m5C related pathways, display disease stage specific and cell type-specific patterns across atherosclerosis, ischemic cardiomyopathy, heart failure, myocarditis, cardiomyopathy, and rheumatic heart disease, highlighting their potential as diagnostic and prognostic biomarkers. Therapeutically, pharmacological modulation of writers and erasers, adeno-associated virus-based gene delivery, and stem cell-based strategies show encouraging preclinical efficacy, while lifestyle interventions such as exercise may optimize the cardiac RNA methylation landscape. In addition, emerging RNA methylation marks, including N¹-methyladenosine (m1A),7-methylguanosine (m7G), N⁶,2'-O-dimethyladenosine (m6Am), and oxidative cytosine derivatives such as 5-hydroxymethylcytosine (hm5C) and 5-formylcytosine (f5C), further expand the RNA modification landscape of cardiovascular remodeling by linking cap-dependent translation, mitochondrial protein synthesis, and stress adaptation. However, major challenges remain, including resolving RNA methylation dynamics at single-nucleotide and single-cell resolution, integrating RNA methylation with other regulatory layers, and achieving precise cardiac delivery with durable safety. With advances in multi-omics, spatial mapping, nanomedicine, and translational research, targeting RNA methylation offers a promising paradigm for improved diagnosis, risk stratification, and personalized therapy in cardiovascular disease.
    Keywords:  Atherosclerosis; Cardiomyopathy; Cardiovascular disease; m1A; m5C; m6A
    DOI:  https://doi.org/10.1007/s11033-026-11865-0
  13. FEBS J. 2026 May 06.
    The different roles of the eS31 ribosomal protein in ribosome biogenesis and translation in Saccharomyces cerevisiae.
    Eduardo Villalobo, Jesús de la Cruz.
      Many ribosomal proteins in yeast possess extensions that protrude from their globular cores to facilitate rRNA folding, ribosome assembly, and translation. Previous work established that the eukaryote-specific N-terminal domain of eS31 harbors a nuclear localization signal; its deletion impairs growth and 40S biogenesis while inducing ribosomal misreading. Gao et al., now provide further insights into this extension, identifying a critical cluster of basic residues essential for elongation fidelity. Furthermore, they demonstrate that full-domain deletion compromises termination through a 'trans-acting disruption' process requiring wild-type eS31. These findings highlight novel mechanisms underlying ribosome heterogeneity and specialization. Comment on: https://doi.org/10.1111/febs.70510.
    Keywords:  N‐terminal domain; SSU; eS31; ribosome biogenesis; ribosome heterogeneity; translation; yeast
    DOI:  https://doi.org/10.1111/febs.70580
  14. J Innate Immun. 2026 May 08. 1-32
    Pyroptosis regulated by m6A modification: implications for pyroptosis-related disease therapy.
    Yujun Zhou, Bo Wei, Sihan Chen, Xinyang Ren, Rongxin Li, Yi Shen, Xiang Wang, Yuzhen Xia, Siyu Cao, Nan Ding.
      Pyroptosis is a lytic and inflammatory form of programmed cell death that is typically initiated by inflammasome activation and executed by gasdermin proteins. It is characterized by cellular swelling, plasma membrane perforation, and the release of intracellular contents. Pyroptosis functions as a "double-edged sword" and plays an essential role in defending the host against pathogen invasion when properly regulated; however, excessive or dysregulated pyroptotic activity can contribute to severe inflammatory pathologies. Aberrant pyroptosis is associated with a range of diseases, including sepsis, inflammatory disorders, cancer, atherosclerosis and neurodegenerative disorders. N6-methyladenosine (m6A) modification is among the most abundant and widespread epigenetic modifications in eukaryotic RNAs and influences multiple stages of gene regulation, from messenger RNA processing to protein synthesis. Emerging evidence indicates that m6A modification plays a regulatory role in pyroptosis, suggesting promising avenues for therapeutic intervention in pyroptosis-related diseases. This review provides a systematic delineation of the signalling pathways regulating pyroptosis and a comprehensive analysis of how m6A modification dynamically regulates this form of inflammatory cell death through its writer, eraser, and reader proteins and explores potential molecular triggers of disease progression. We further aimed to elucidate the pathophysiological significance of m6A-mediated regulation of pyroptosis in disease and identify novel therapeutic targets.
    DOI:  https://doi.org/10.1159/000552343
  15. Nat Plants. 2026 May 08.
    CDS-localized m6A drives co-translational RNA decay to relieve biotic and abiotic endoplasmic reticulum stresses.
    Songxiao Zhong, Tae Rin Oh, Xindi Li, Jinming Zhang, Suk Won Choi, Chuyun Gao, Xu Peng, Juan Dong, Chuan He, Xiuren Zhang.
      The endoplasmic reticulum (ER) mitigates stress typically through unfolded protein response (UPR) and ER-associated degradation (ERAD) pathways, yet post-transcriptional regulation of ER stress remains poorly defined. N6-methyladenosine (m6A) modification, predominantly enriched near stop codons, can govern mRNA fates via P-bodies or stress granules in stress conditions. m6A also occurs within coding sequences (CDS-m6A), but its role remains unappreciated in plants. Here we demonstrate that m6A ablation sensitizes Arabidopsis ER stress despite normal UPR and ERAD activities. Mechanistically, CDS-m6A co-localizes with ribosome stalling sites and directs co-translational RNA decay (CTRD). Under stress, activation of m6A-triggered CTRD accelerates clearance of ER-engaged transcripts, thereby alleviating translational overload. During geminivirus infection, which increases translational demand on ER, m6A-triggered CTRD also targets viral RNAs, restricting their accumulation, translation and disease progression. Thus, CDS-m6A functions as a pivotal regulator of ER-linked RNA surveillance, establishing an organelle-specific mechanism that integrates RNA stability, protein homeostasis and antiviral defence.
    DOI:  https://doi.org/10.1038/s41477-026-02299-4
  16. Trends Cell Biol. 2026 May 07. pii: S0962-8924(26)00061-9. [Epub ahead of print]
    Stress-induced breakup: tRNA-derived small RNAs in biology.
    Guoping Li, Tian Hao, Pavel Ivanov, Saumya Das.
      The cleavage of full-length transfer RNAs generates functional small RNAs called tRNA-derived small RNAs (tsRNAs or tDRs). This review synthesizes recent advances in our understanding of tDRs, summarizing the molecular mechanisms of their biogenesis and illuminating their function in modulating pathways important in the cellular stress response. Key structural motifs appear to be critical determinants of tDR function by modulating binding to partner proteins and RNAs. Finally, the role of tDRs in the pathogenesis of various diseases and the feasibility of targeting them with novel molecular tools are discussed. In summary, tDRs are an evolutionarily conserved class of small RNAs important for the cellular response to stress and are emerging as a promising target for human diseases.
    Keywords:  RNA therapeutics; noncoding small RNAs; stress response; tRNA fragments
    DOI:  https://doi.org/10.1016/j.tcb.2026.04.003
  17. Pharmacol Res. 2026 May 05. pii: S1043-6618(26)00143-X. [Epub ahead of print] 108228
    ISRIB as a Prototype eIF2B Activator: Pharmacology, Mechanisms, and Translational Potential in Aging-Related Cognitive Disorders.
    Peng-Fei Zhu, Zhaoru Lyu, Qingsong Wang, Shiyong Li, Xuan Wang, Ailin Luo.
      Aging-related cognitive disorders have been increasingly linked to maladaptive stress pathways that persistently impair synaptic protein synthesis and plasticity. The integrated stress response (ISR) links various stressors to downstream translational reprogramming through the phosphorylation of eIF2α. Acute ISR activation can be protective, while chronic ISR activation may confine neurons and glial cells to hypo-plastic states, impairing learning and memory function. ISRIB is a prototype small molecule that activates eIF2B and restores translation homeostasis, providing a viable framework for "tuning" ISR output rather than indiscriminately blocking stress signaling. This review summarizes ISR biology in the aging brain, emphasizes cell-type heterogeneity, and evaluates the evidence for ISRIB across various conditions, including normal aging, Alzheimer's disease, vascular cognitive impairment, synucleinopathies, perioperative neurocognitive disorders, and related conditions with shared ISR pathology. We then discuss dosing, safety, optimization, limitations, translational biomarkers, and lessons from emerging clinical-stage eIF2B activators. Finally, we propose precision and combination strategies to tailor ISR modulation to disease stage, pathological context, and therapeutic window, aiming to provide new directions and a theoretical basis for the treatment of aging-related cognitive disorders.
    Keywords:  ISRIB; Integrated stress response; aging-related cognitive dysfunction; eIF2B; synaptic plasticity; translational control
    DOI:  https://doi.org/10.1016/j.phrs.2026.108228
  18. Curr Top Dev Biol. 2026 ;pii: S0070-2153(26)00001-3. [Epub ahead of print]168 371-428
    Protein synthesis during mouse spermatogenesis.
    Lele Yang, Kun Hou, Tin-Lap Lee, Huayu Qi.
      Spermatogenesis is composed of three consecutive stages, mitosis, meiosis and spermiogenesis, during which spermatogenic cells undergo continuous molecular and cellular transformation. Regulation of gene expression has been underlying major molecular mechanisms that govern the progressive cell fate determination during spermatogenesis. Besides epigenetic and transcriptional controls, the un-coupled transcription and translation is a common phenomenon conserved across phyla during spermatogenesis. Translational regulation determines the dynamic proteomic landscapes in spermatogenic cells. Aberrant protein synthesis caused by mutations in RNA binding proteins (RBPs) and translation regulators often cast detrimental effects on spermatogenesis in a stage-specific manner, leading to male infertility. Regulation of gene expression at the post-transcriptional and translational levels bear advantages of fast and flexible responses to changing environment, coordination of cellular states including energy and nutrient availability, preservation of genomic fidelity and quantitative and qualitative control of proteins, the functional units of the cell. How cell type-specific translation is regulated during spermatogenesis is largely unclear. In this review, we will first introduce general features of protein synthesis and what have been revealed during mouse spermatogenesis when aberrant protein synthesis occurred. We will then analyze the differential signaling pathways and intracellular factors that cooperatively regulate proteomic landscapes in spermatogenic cells at various stages of spermatogenesis. Protein synthesis is a fundamental mechanism underlying cell fate determination. Taking advantage of current advancements in methodology, future research in this area will unveil the design principles that govern how cells program and maintain functional proteome during development and disease.
    Keywords:  AKT-mTORC1; Cell fate determination; Differentiation; Meiosis; Protein kinase A; Protein synthesis; Self-renewal; Spermatogenesis; Spermatogonial stem cells; Spermiogenesis
    DOI:  https://doi.org/10.1016/bs.ctdb.2026.01.001
  19. Neuro Oncol. 2026 May 02. pii: noag097. [Epub ahead of print]
    Phase separation of TRNAU1AP protein sustains selenoprotein translation and promotes glioblastoma tumorigenesis.
    Xiaowei Zhang, Li Li, Linlin Li, Shijun Yu, Taohui Ouyang, Xiao Han, Richard I Joh, Yiwen Chen, Huizhi Wang, Suyun Huang.
       BACKGROUND: Glioblastoma (GBM) depends on selenoproteins, yet the mechanisms underlying their dysregulation remain poorly understood. The tRNA-binding protein TRNAU1AP also remains largely uncharacterized, with its mechanistic functions in in vivo tumorigenesis undefined. Additionally, while IGF2BP3 is the most dysregulated m6A reader in GBM, the pathways through which it promotes glioblastoma stem cell (GSC) self-renewal have yet to be elucidated.
    METHODS: TRNAU1AP expression in human GBMs and public datasets was analyzed by Western blotting, immunohistochemistry, and gene expression profiling. Functions of TRNAU1AP in GSCs were evaluated through gain- and loss-of-function assays assessing proliferation, self-renewal, and tumorigenicity. Proteomics, spatial transcriptomics, RNA immunoprecipitation, and polysome profiling were employed to investigate TRNAU1AP-mediated regulation of selenoprotein synthesis. RNA immunoprecipitation and phase-separation assays were used to characterize the TRNAU1AP-EEFSEC interaction. Multi-omics and RNA stability analyses were performed to elucidate IGF2BP3-dependent regulation of TRNAU1AP expression.
    RESULTS: TRNAU1AP is essential for the proliferation, stemness, and tumorigenesis of GSCs and is associated with poor patient survival. TRNAU1AP interacts with EEFSEC to form a phase-separated complex that enhances EEFSEC binding to sec-tRNAsec, thereby promoting the translation of several selenoproteins. These selenoproteins act as key effectors mediating the oncogenic functions of TRNAU1AP. Furthermore, IGF2BP3 upregulates TRNAU1AP expression through m⁶A-dependent transcript stabilization, leading to increased selenoprotein synthesis and enhanced GSC stemness and tumorigenic potential.
    CONCLUSION: These findings establish novel oncogenic roles of TRNAU1AP, and reveal that IGF2BP3-TRNAU1AP coupling constitutes an important mechanism for the selenoprotein synthesis and for gliomagenesis, thereby advancing the understanding of RNA-binding proteins in cancer biology.
    Keywords:  Glioblastoma stem cells; Phase separation; Selenoproteins; TRNAU1AP; m6A
    DOI:  https://doi.org/10.1093/neuonc/noag097
  20. RSC Chem Biol. 2026 Apr 17.
    Enhancing mRNA stability and translational potential through tailored modifications at the 3' end.
    Olga Perzanowska, Joanna Kowalska, Jacek Jemielity.
      Poly(A) tails regulate mRNA turnover and translation through multiple RNA-protein interactions, and deadenylation is the initiating step of the major cytoplasmic decay pathways. Here, we report a simple post-transcriptional strategy to protect the 3' end of synthetic mRNA by enzymatically ligating short, chemically modified 5'-phosphorylated dinucleotides. Using T4 RNA ligase 1, we attached 2'-O-methyl and/or phosphorothioate containing A- or G-dinucleotides to the 3' end of model oligoadenylates and to an IVT Gaussia luciferase (GLuc) mRNA bearing an ∼150-nt poly(A) tail. All ligated products showed strong resistance to human CNOT7-mediated deadenylation in vitro, whereas the unmodified control mRNA underwent poly(A) removal. In rabbit reticulocyte lysate, 3'-modified GLuc mRNAs translated comparably to the control, indicating minimal interference with the translational machinery. In mammalian cells (A549, JAWSII and HEK293), the protein output depended on the dinucleotide structure and cell type; two adenosine donors-pApAm and the D1 phosphorothioate stereoisomer pApsAm-consistently performed best, increasing the cumulative GLuc production up to 163% in HEK293 and up to 79% in A549. These results establish dinucleotide ligation as a minimal and modular 3'-end engineering approach that enhances resistance to deadenylation and can improve the translational performance of therapeutic mRNA candidates.
    DOI:  https://doi.org/10.1039/d6cb00033a
  21. Nucleic Acids Res. 2026 May 05. pii: gkag376. [Epub ahead of print]54(9):
    Structural and biochemical characterization of yeast Tcd enzymes installing the post-transcriptional modification ct6A in tRNA.
    Julia Hirschmann, Rachel Sonntag, Matthias Heiss, Ewa Wegrzyn, Wolfgang Heinemeyer, Thomas Carell, Eva M Huber.
      Post-transcriptional modifications near the anticodon of transfer ribonucleic acids (tRNAs) ensure translation fidelity and accuracy. For instance, at position 37, the universally conserved and essential nucleoside N6-threonylcarbamoyladenosine (t6A) supports decoding of ANN triplets. In some organisms t6A is converted to cyclic t6A (ct6A), but only little is known about this ATP-dependent reaction and the corresponding threonylcarbamoyladenosine dehydratases (Tcds). We here show that yeast Tcds localize to the outer mitochondrial membrane and co-purify with tRNAs recognizing ANN codons. Depending on the number of TCD genes in the genome, the proteins form V-shaped hetero- or homodimers, of which at least one subunit binds and modifies tRNAs. The C-terminal, monomeric domain shares similarities with Cas9-endonucleases and assists tRNA recognition, while the N-terminal domain mediates dimerization and contains the active site. Structure-based mutagenesis and activity assays imply that yeast Tcds lack a catalytic cysteine and do not covalently bind their substrate as proposed for Escherichia coli TcdA.
    DOI:  https://doi.org/10.1093/nar/gkag376
  22. Chem Res Toxicol. 2026 May 04.
    The Expanding Landscape of ADP-Ribosylation: Protein, DNA, RNA, and Mitochondrial Regulation.
    Yi-Cheng Sin, Linlin Zhao.
      ADP-ribosylation is an essential post-translational modification that contributes to key cellular processes, such as DNA damage repair, cell-cycle progression, chromatin remodeling, mitochondrial function, and immune responses in mammalian cells. This modification derives from NAD+ and is regulated by dedicated writer, eraser, and reader proteins that govern its installation, removal, and recognition. Traditionally viewed as a protein-centered modification, ADP-ribosylation has recently been extended to nucleic acids, with ADP-ribosylated DNA and RNA now identified in both mammalian and bacterial systems. These discoveries reveal previously underappreciated layers of nucleic acid-based regulation and suggest that NAD+-dependent chemistry integrates genome maintenance, RNA metabolism, and cellular stress responses. In this review, we first outline the major mammalian ADP-ribosylation machineries, including the families of writer, eraser, and reader proteins, and discuss how their activities are coordinated. We then examine emerging roles of ADP-ribosylation in mitochondria, with a focus on mitochondrial DNA repair and metabolic control. Finally, we highlight recent advances in understanding NAD+-dependent modifications of DNA and RNA in mammalian and bacterial cells, including terminal and nucleobase-linked ADP-ribosylation and NAD capping, and discuss outstanding questions regarding their physiological functions and interplay with protein post-translational modification and other nucleic acid modifications.
    DOI:  https://doi.org/10.1021/acs.chemrestox.6c00176
  23. Mol Biol Rep. 2026 May 02. pii: 706. [Epub ahead of print]53(1):
    The role of protein prenylation in kidney diseases: Molecular basis and therapeutic implications.
    Rohan Bhadange, Anil Bhanudas Gaikwad.
      Kidney diseases may lead to a life-threatening condition, with their global prevalence increasing day by day. The progressive nature of kidney diseases is driven by a complex interplay of cellular and molecular events, among which protein prenylation plays a pivotal role. Protein prenylation, a lipid-mediated post-translational modification, is essential for the functional regulation of small guanosine triphosphatase binding proteins, including Ras, Rac, Rab, and Rho, which govern cell signaling, proliferation, and membrane dynamics. Aberrant prenylation disrupts these signaling cascades, contributing to podocyte injury, mitochondrial dysfunction, oxidative stress, and renal fibrosis, among others. This review provides an integrated overview of recent advancements in protein prenylation, the effects of these modifications on renal physiology, emerging insights into how altered prenylation drives kidney disease progression and identifies therapeutic strategies targeting this modification. Moreover, we emphasized the potential pharmacological interventions, including bisphosphonates, statins, and others, providing multitargeted therapeutic benefits in various forms of kidney diseases. This review underscores the translational potential of modulating protein prenylation as a novel therapeutic strategy for the management of kidney diseases and for improving clinical outcomes.
    Keywords:  Endothelial dysfunction; Fibrosis; Inflammation; Kidney diseases; Post-translational modification; Protein prenylation; Therapeutic strategies
    DOI:  https://doi.org/10.1007/s11033-026-11812-z
  24. NPJ Parkinsons Dis. 2026 May 06.
    The epitranscriptomic m6A RNA modification modulates the synapse in ageing and in a mouse model of synucleinopathy.
    Avika Chopra, Mary Xylaki, Fanzheng Yin, Ricardo Castro-Hernández, Madiha Merghani, Valentina Grande, Brit Mollenhauer, André Fischer, Tiago F Outeiro.
      N6-methyladenosine (m6A) is the most abundant transcriptional modification in eukaryotic RNA, regulating RNA fate. While the functions of m6A in the development of the mammalian brain have been extensively studied, its role in synaptic plasticity, and brain function remain underexplored. The involvement of this modification in Parkinson's disease and other synucleinopathies has only recently been studied, and needs further investigation. Here, we investigated the m6A epitranscriptome using MeRIP-seq in A30P-aSyn transgenic mice (aSyn Tg). We observed hypermethylation of synaptic genes in young aSyn Tg mice compared to age-matched control mice. The methylation was reduced during ageing. Using immunofluorescence imaging and biochemical analysis, we further investigated the levels and distribution of m6A regulatory enzymes-writer, METTL3, reader, YTHDF1, and eraser, FTO, in the cortex, striatum, hippocampus, and cerebellum of aSyn Tg and control mice, and in primary cortical neuronal cultures. While the levels of these proteins were similar, METTL3 was found in the nucleus and in the post-synaptic compartment in neurons, suggesting it may play a role in methylation at the post-synapse. Our findings suggest that alterations in the regulation of m6A RNA methylation may be associated with neurodegeneration and ageing and it may play a significant role at the synapse.
    DOI:  https://doi.org/10.1038/s41531-026-01362-3
  25. Nucleic Acids Res. 2026 May 05. pii: gkag404. [Epub ahead of print]54(9):
    Yield and fidelity of early steps of ribosome-free translation depend on the RNA anchoring.
    Nikolaos Giannakopoulos, Patrick Haas, Clemens Richert.
      Before the translational machinery came into being, a simpler form of reading RNA sequences to instruct peptide synthesis must have existed. What this earliest form of translation was is unclear. Ribosome-free synthesis, relying solely on Watson-Crick base pairing and chemical reactivity, is a likely candidate. The established version of this process involves chain growth at the C-terminus of N-terminally anchored peptides. Here, we show that ribosome- and enzyme-free translation via chain growth at the N-terminus of C-terminally anchored peptides is also feasible. Yields for the formation of dipeptides via the latter process were between 6% and 46%, though, as compared to 60%-99% for dipeptides with opposite strand growth orientation. Translation fidelity to dipeptides was also lower, with just 55%-84% correct incorporation, versus 64%-92% for N-terminally linked dipeptides. On the tripeptide level, the preference for C-terminal chain growth was smaller, suggesting that only the very first step has a strong bias for N-terminal anchoring. Finally, mixed anhydride pre-activation was found to be an alternative to in situ activation for peptidyl RNAs. This data sheds light on putative early steps in the evolution of translation.
    DOI:  https://doi.org/10.1093/nar/gkag404
  26. bioRxiv. 2026 Apr 22. pii: 2026.04.21.719927. [Epub ahead of print]
    ZBP1's Inability to Convert Unmodified RNAs to the Z-form Underlies a Balanced Mechanism of RNA Recognition with ADAR1.
    Jeffrey B Krall, Lily G Beck, Parker J Nichols, Quentin Vicens, Morkos A Henen, Beat Vögeli.
      Z-DNA Binding Protein 1 (ZBP1) is a critical pattern recognition receptor within the innate immune response to viral infection. ZBP1 senses foreign nucleic acids in the unusual, left-handed Z-conformation via binding through its N-terminal Zα1 and Zα2 domains and activates downstream pro-pyroptotic, -apoptotic, and -necroptotic pathways to initiate cell death and allow for viral clearance. Both dsDNA and dsRNA can adopt the Z-conformation, however, the conformational change is energetically expensive, especially for dsRNA, and typically requires chemical modifications or protein binding to induce a right-to-left-handed conversion and stabilization. ZBP1 has been previously shown to bind and convert B-DNA to the Z-conformation and was assumed to be able to convert A-RNA as well, despite the lack of experimental validation. Here, we use a variety of Nuclear Magnetic Resonance (NMR) and other biophysical and biochemical experiments to characterize the Z-DNA and Z-RNA binding properties of ZBP1's Zα1 and Zα2 domains. While ZBP1's Zα domains are able to convert and stabilize unmodified dsDNA in the Z-conformation, both domains are incapable of flipping unmodified A-conformation dsRNA. We show that ZBP1's Zα domains require dsRNAs with Z-promoting chemical modification in order for them to bind and stabilize the Z-conformation. These results contrast with the Zα domain from Adenosine Deaminase Acting on RNA 1 (ADAR1), which can bind and flip both dsDNA and dsRNA into the Z-conformation, potentially indicating finely tuned competition between ADAR1 and ZBP1 for pro-survival and pro-death outcomes, respectively. This work highlights the functional variability of Zα domains and narrows down the potential physiological substrates of ZBP1 in infection and disease.
    Graphical:
    DOI:  https://doi.org/10.64898/2026.04.21.719927
  27. RNA Biol. 2026 May 07.
    Evaluating Malat1-derived 3'end sequences for functional transgene expression in human cells using synthetic mRNA delivery.
    Julia Rosemann, Gwendolin Thordis Jahr, Jana Macho, Monika Haemmerle, Tony Gutschner.
      The poly(A) tail is a key structural element found in almost all mammalian messenger RNAs, required for stabilizing the transcript and enhancing translation. Here, we evaluate poly(A) replacement strategies based on sequence elements derived from the long non-coding RNA Malat1. Malat1 undergoes RNase P processing to generate a 3' end protected by a conserved triple helix. Importantly, this triple helix structure was shown to enhance translation when placed downstream of an open reading frame. We compared Malat1-derived 3' end motifs with canonical poly(A) tails incorporated into a synthetic reporter RNA encoding a green fluorescent protein. Our results corroborate the central role of the poly(A) tail for efficient expression, showing that the tested Malat1-derived motifs can generally support translation of the reporter mRNA, although they consistently underperform compared to canonical poly(A) tails. Future work should optimize triplex sequence and folding to enhance translation capacity, test additional triplex structures, and explore small molecule to regulate stability and translation of triplex-containing RNAs for applications in synthetic biology and RNA-based therapeutics.
    Keywords:  Protein translation; mascRNA; poly(a) tail; polyadenylation; triple helix
    DOI:  https://doi.org/10.1080/15476286.2026.2670832
  28. Antioxidants (Basel). 2026 Apr 08. pii: 459. [Epub ahead of print]15(4):
    Therapy as a State-Generator: Dynamic Phenotypic Landscapes and Adaptive Stress Circuits in Chemotherapy Resistance of Breast Cancer.
    Moon Nyeo Park.
      Chemotherapy resistance remains a major obstacle to durable cancer control, yet its underlying mechanisms cannot be fully explained by genetic mutations alone. Increasing evidence suggests that therapeutic stress induces dynamic adaptive programs that reshape tumor phenotypic landscapes. Here, we propose a systems-level framework in which chemotherapy resistance emerges from the stabilization of interconnected stress-response circuits integrating redox signaling, metabolic reprogramming, and transcriptional plasticity. In this model, cytotoxic therapies function as state-generating perturbations that elevate oxidative stress and activate adaptive buffering systems, including NADPH-dependent redox homeostasis, replication stress tolerance, and integrated stress response (ISR)-mediated translational reprogramming. These adaptive modules collectively expand the accessibility of therapy-tolerant phenotypic states within tumor cell populations. Importantly, these circuits coordinate mitochondrial redox homeostasis, metabolic NADPH regeneration, and epigenetic-transcriptional plasticity to sustain cellular survival under persistent oxidative pressure. Such adaptive redox networks not only stabilize stress-tolerant phenotypes but also create vulnerabilities that can be therapeutically exploited. From a translational perspective, this framework suggests that effective strategies to overcome chemotherapy resistance should move beyond single-target inhibition and instead focus on circuit-guided therapeutic interventions that simultaneously destabilize redox buffering systems, constrain phenotypic plasticity, and disrupt metabolic stress adaptation. By conceptualizing therapy resistance as a dynamic redox-regulated state-space phenomenon, this model provides a mechanistic foundation for the development of evolution-aware and plasticity-constraining therapeutic strategies. Targeting the coordinated redox-metabolic-translational circuits that maintain tumor adaptability may therefore represent a promising direction for next-generation redox therapeutics in cancer.
    Keywords:  breast cancer; chemotherapy resistance; integrated stress response; metabolic reprogramming; phenotypic plasticity; redox signaling
    DOI:  https://doi.org/10.3390/antiox15040459
  29. NAR Mol Med. 2026 Apr;3(2): ugag021
    The dynamics and strategy of RNA replication in astroviruses.
    David Noyvert, Imran M Darr, Ksenia Fominykh, Jacqueline Hankinson, Nina Lukhovitskaya, Andrew E Firth, Valeria Lulla.
      Astroviruses are positive-sense single-stranded RNA viruses that cause significant disease across avian and mammalian hosts, yet their replication mechanisms remain poorly understood. The replication of astrovirus RNA occurs via a double-stranded RNA intermediate that is used as a template for the synthesis of new positive-sense RNA, which is covalently linked to the virus-encoded protein VPg. These viruses also produce a capsid-encoding subgenomic (sg) RNA that is 3'-coterminal with the genomic RNA. The mechanisms by which the astrovirus sgRNA is produced and regulated during infection have not yet been characterized. Using high-throughput sequencing of RNA from cells infected with each of five different astrovirus strains, we demonstrate that the presence of a (-)sgRNA is a conserved feature of infection, supporting a premature termination model of subgenomic RNA production. A pronounced pile-up in the mapping positions of the 3' ends of negative-sense RNA fragments marks the precise 3' terminus of the (-)sgRNA. We investigate the relative abundance and replication dynamics of positive and negative RNA species during the virus life cycle, and perform a mutational analysis of conserved residues in the genomic and subgenomic 5' termini. Together, this work elucidates the dynamics of genomic and subgenomic RNA synthesis during astrovirus infection.
    DOI:  https://doi.org/10.1093/narmme/ugag021
  30. J Physiol. 2026 May 07.
    The deletion of HSP60 in cholinergic neurons alleviates LPS-induced depressive-like behaviours in mice by reducing neuroinflammation.
    Xiangzan Wei, Xiaoni Zhong, Yu Ouyang, Yongxiang Liu, Weirong Qin.
      Depression is a significant global health issue characterized by complex underlying mechanisms. This study aimed to investigate the role of cholinergic neuron-specific heat shock protein 60 (HSP60) in modulating lipopolysaccharide (LPS)-induced neuroinflammation and depressive-like behaviours in mice. Cholinergic neuron-specific HSP60 knockout mice were generated by crossing Hsp60-flox mice with Chat-cre mice. Genotyping confirmed the successful creation of the knockout. The effects of LPS on weight loss, behavioural changes, cytokine levels, neuroinflammation markers and signalling pathway proteins were assessed. Behavioural assessments included the tail suspension test and sucrose preference test. HSP60 knockout mice exhibited mitigated weight loss in response to LPS. Behavioural tests indicated that HSP60 deficiency alleviated LPS-mediated depressive-like behaviours without affecting locomotor activity. In the hippocampus, LPS treatment significantly altered cytokine levels, increasing pro-inflammatory cytokines at the same time as decreasing anti-inflammatory cytokines. HSP60 knockout mice partially reversed these effects, showing increased anti-inflammatory and decreased pro-inflammatory cytokines. LPS-induced upregulation of neuroinflammation markers such as glial fibrillary acidic protein, NLRP3 (i.e. NOD-, LRR- and pyrin domain-containing protein 3) and p-IKKα/β [i.e. the phosphorylated forms of the catalytic subunits of the IκB kinase (IKK) complex, specifically IKKα (CHUK) and IKKβ] was significantly reduced in HSP60 knockout mice. Additionally, LPS-induced elevation of phosphorylated eukaryotic translation initiation factor 2α levels in the hippocampus was attenuated by HSP60 deficiency, without affecting other signalling pathway proteins. These findings suggest that HSP60 in cholinergic neurons plays a critical role in regulating LPS-induced neuroinflammation and depressive-like behaviours. Targeting HSP60 in cholinergic neurons may provide a therapeutic approach for mitigating neuroinflammation and associated depressive symptoms. KEY POINTS: Specific knockout of HSP60 in cholinergic neurons could protect against LPS-induced physiological and behavioral impairments, including mitigated weight loss, improved depressive-like behaviors, and unaffected locomotor activity. Cholinergic neuron-specific HSP60 deletion could attenuate neuroinflammation by reversing LPS-induced cytokine imbalance, suppressing key inflammatory markers (GFAP, NLRP3, cGAS, p-IKKα/β), and crucially, by preserving hippocampal acetylcholine levels, a key neurotransmitter with established anti-inflammatory properties. HSP60 deficiency selectively reduces the LPS-induced phosphorylation of the eukaryotic translation initiation factor 2α (p-eIF2α) in the hippocampus, indicating a targeted modulation of the cellular stress and protein synthesis regulation pathway, without altering other major signaling molecules.
    Keywords:  HSP60; cholinergic neuron; depression; neuroinflammation
    DOI:  https://doi.org/10.1113/JP290049
  31. Biophys Chem. 2026 Apr 30. pii: S0301-4622(26)00077-3. [Epub ahead of print]335 107644
    Unveiling the adaptive structure-function synergy in thermophilic translation initiation factor 1: A molecular dynamics framework.
    Arpan Maity, Aveepsa Sengupta, Pushan Chatterjee, Mamta Rani, Ashutosh Kumar.
      The translation mechanism in thermophilic bacteria requires unique adaptations to maintain its efficiency under extreme temperatures. Stabilised ribosomal interactions and recognition of the start codon are facilitated by Initiation Factor 1 (IF1). However, the underlying atomistic foundation behind its thermal resilience is not yet fully elucidated. In this study, we performed comprehensive molecular dynamics simulations (1000 ns each, in triplicate) to evaluate the dynamic properties of IF1 from the thermophilic bacterium Thermoanaerobacterium thermosaccharolyticum (TT_IF1) compared to its mesophilic counterpart (FK_IF1, IF1 from Flavobacterium kingsejongi). Our analyses point to enhanced structural rigidity in TT_IF1, stabilised by an expanded network of hydrogen bonds and salt bridges. Principal component analysis highlighted restricted conformational fluctuations, suggesting evolutionary optimisation to minimise entropy-driven destabilisation at elevated temperatures. Furthermore, residue-level flexibility profiles indicated that TT_IF1 maintains a delicate balance between stability and functional plasticity, preserving its ability to interact with ribosomal RNA while resisting thermal unfolding. These findings provide mechanistic insights into the molecular strategies underlying thermophilic adaptation of translation initiation factors. Beyond fundamental biology, this work establishes a framework for engineering thermostable protein variants with potential applications in synthetic biology and industrial biotechnology.
    Keywords:  Initiation factor 1; Structural–functional interplay; Thermoanaerobacterium thermosaccharolyticum; Thermophiles; Thermophilic adaptation
    DOI:  https://doi.org/10.1016/j.bpc.2026.107644
  32. Sci Rep. 2026 May 05.
    Architectural principles of the ribosomal large subunit revealed by A-helix spatial organization.
    Yi-Shan Lan, Jing-Hong Tu, Ying-Chi Wang, Chiaolong Hsiao.
      The ribosome, biology's universal translation apparatus, is one of the deepest molecular imprints of life's early evolution. Among its structural motifs, the RNA A-helix is the most abundant and fundamental architectural element. Here, we investigate how A-helices collectively shape the three-dimensional organization of the large ribosomal subunit (LSU) across bacteria, archaea, eukaryotes, and mitochondria. By mapping each A-helix onto a centroid-based geometric framework, we identify a conserved peak-centered radial distribution of A-helices that characterizes the spatial organization of LSUs. Applying this approach across diverse ribosomes reveals reproducible architectural states while accommodating lineage-specific structural variation. Notably, mitochondrial LSUs exhibit remodeled radial distributions while retaining the core architectural pattern, consistent with extensive structural adaptation accompanying mitochondrial ribosome evolution. Together, these findings establish the A-helix as a fundamental architectural element of the LSU and provide a generalizable framework for describing ribosomal structure across evolutionary diversity.
    DOI:  https://doi.org/10.1038/s41598-026-52028-2
  33. Curr Biol. 2026 May 04. pii: S0960-9822(26)00380-5. [Epub ahead of print]36(9): R386-R388
    Giant viruses: Bringing your own translation machinery makes infection less stressful.
    Shivani Khosla, Matthew D Daugherty.
      All viruses rely on host ribosomes for mRNA translation. A new study reveals that some giant viruses encode their own version of a translation initiation complex that selectively promotes viral protein production and facilitates stress resilience.
    DOI:  https://doi.org/10.1016/j.cub.2026.03.060
  34. Cell Commun Signal. 2026 May 09.
    CELF family of RNA-binding proteins: roles in disease biology and potential for therapeutic intervention.
    Yukang Ma, Chi Ma, Aobo Yang, Yiming Chen, Jiajun Gao, Qunshu Wang, Zhixi Wei, Meiling Gao, Xiangling Xing, Wancheng Liu.
      The CUG-BP and Elav-like (CELF) family of RNA-binding proteins are key regulators of post-transcriptional gene expression, coordinating alternative splicing, mRNA stability, and translation. Although individual members, particularly CELF1 and CELF2, have been extensively characterized, a systematic, paralog-resolved integration of structural determinants, regulatory mechanisms, and disease relevance across all six CELF proteins remains limited. Here, we establish an integrative framework linking conserved RNA recognition motifs and divergent linker domains to context-dependent regulatory outputs, mediated by phosphorylation, nucleocytoplasmic dynamics, and RNA network interactions. We further highlight the neuron-enriched CELF3-CELF6 subfamily, consolidating emerging evidence that extends their roles beyond neural splicing into cancer-associated regulatory programs. Notably, we delineate functional divergence within the family, with CELF1 frequently acting as an oncogenic driver in contrast to the tumor-suppressive role of CELF2, while positioning less-characterized paralogs within this regulatory spectrum. Together, this work defines a unified structure-function-disease axis for CELF proteins and provides a conceptual framework for their prognostic and therapeutic exploitation. However, current CELF-targeted strategies remain largely preclinical and face key translational challenges, including paralog selectivity, off-target effects, and delivery barriers such as limited blood-brain barrier penetration. Accordingly, the most immediate clinical utility of CELF biology is likely to lie in biomarker development and patient stratification, rather than direct therapeutic intervention.
    Keywords:  Alternative splicing; CELFs; Cancer; RNA-binding proteins; Therapeutic targets
    DOI:  https://doi.org/10.1186/s12964-026-02924-x
  35. bioRxiv. 2026 Apr 27. pii: 2026.04.26.720784. [Epub ahead of print]
    Mechanism of nucleolytic degradation of human ribosomes.
    Frances F Diehl, Allen R Buskirk, Rachel Green.
      Stresses like starvation trigger degradation of mature 40S ribosomes, requiring the coordinated breakdown of large and 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 the 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 which 3' oligo(uridine) tailing drives decay of rRNA from ribosomes.
    DOI:  https://doi.org/10.64898/2026.04.26.720784
  36. Mol Med Rep. 2026 Jul;pii: 186. [Epub ahead of print]34(1):
    Multifaceted regulatory role of proline‑ and glutamine-rich splicing factor in tumors (Review).
    Shilin Zhang, Zhenhua Li, Li Fu.
      Proline‑ and glutamine‑rich splicing factor (SFPQ) is an RNA‑binding protein that is predominantly localized in the nucleus and plays a multifaceted regulatory role in the process of gene expression. The functions of SFPQ include the promotion or inhibition of gene transcription, pre‑mRNA splicing, mRNA processing, transport and localization, and translation. The primary impact of SFPQ on cellular processes is the regulation of cell cycle progression and apoptosis. In addition, SFPQ represents an important element of paraspeckles, exerting a notable influence on gene expression within the nucleus. The expression of SFPQ is altered in tumors, promoting the development and drug resistance of tumors in various ways, notably altering the prognosis of patients. In the present review, the fundamental physiological functions of SFPQ and its particular effects on tumorigenesis and development are discussed.
    Keywords:  apoptosis; cancer; drug resistance; paraspeckle; proline‑ and glutamine‑rich splicing factor
    DOI:  https://doi.org/10.3892/mmr.2026.13896
  37. Angew Chem Int Ed Engl. 2026 May 04. e1434064
    Structure-Encoded Oxidation Enables Nucleotide-Resolved RNA Editing, Conjugation, and Structural Probing.
    Jieyi Shentu, Ziyi Jiang, Qilong Tan, Linglan Fang.
      RNA oxidation is pervasive in stress and disease biology and has also been harnessed in chemical biology through proximity labeling, ligand-directed photochemistry, and oxidative RNA targeting. In most settings, the regioselectivity is specified by spatial proximity or a specialized RNA-binding ligand, and the resulting modification is typically distributed across a local region rather than at a designated nucleotide. Here we show that, with selected oxidants, RNA secondary structure can itself serve as a programmable handle to control RNA oxidation site-selectively. We define practical structure-reactivity rules that determine which guanosine is oxidized and which lesions predominate, based on loop geometry and oxidant identity. Guided by these rules, we develop LOCAL (Localized Oxidation Constrained at Loops), a DNA-programmed, postsynthetic method that directs guanosine oxidation to predetermined sites in transcribed RNAs with nucleotide-resolved selectivity. LOCAL enables oxidative base editing to modulate RNA interactions and stability, provides a plug-and-play tool for site-specific bioconjugation via nucleophile trapping of oxidized guanosines, and serves as a blue-light-gated, guanosine-focused structural readout of RNA single-strandedness and ligand-induced structural changes. Together, these results position RNA oxidation as a nucleotide-resolved, structure-encoded reaction manifold that complements existing ligand-encoded oxidative targeting chemistry, and 2´-OH- and enzyme-based RNA chemistries.
    Keywords:  RNA structure; bioconjugation; oxidation; posttranscriptional modification
    DOI:  https://doi.org/10.1002/anie.1434064
  38. Int J Biol Macromol. 2026 May 06. pii: S0141-8130(26)02206-3. [Epub ahead of print] 152279
    Translational hub ribosomal protein S5 promotes glioblastoma progression by affecting translation patterns.
    Lin Wang, An Yan, Jing-Hao Suo, Jin-Feng Song, Ze-Fan Jing, Kun-Nian Ran, Bin Yin, Lin Hou, Wei Han, Xiao-Zhong Peng.
      Ribosomes play pivotal roles in normal physiology, cellular responses to stimuli, and disease pathogenesis. Ribosome biogenesis is essential for cancer cell growth. Although several ribosomal proteins have been implicated in tumorigenesis, their functional roles in glioblastoma multiforme (GBM) remain poorly understood. Using a CRISPR-based screening system targeting RNA-binding proteins (RBPs) in three glioma cell lines (LN229, U118MG, and T98G), we identified essential RBPs for glioma growth and observed significant enrichment of ribosomal proteins. Analysis of TCGA datasets (LGG & GBM, n = 636) revealed that high RPS5 expression was associated with malignant progression; survival analysis via GEPIA (n = 676) showed that elevated RPS5 correlated with poor overall survival (p = 4 × 10-6) and disease-free survival (p = 6.9 × 10-4). Functional experiments demonstrated that RPS5 silencing inhibited glioma malignant phenotypes both in vitro and in vivo. Mechanistically, RPS5 regulated translational processes in glioma cells, including start/stop codon recognition and cap-independent translation. Ribosome profiling (n = 3) coupled with RNA sequencing revealed that RPS5 enhanced the translational efficiency of SLC4A7 and MAK16, driving GBM progression. Furthermore, bicistronic reporter assays with rigorous controls (promoter-less vector, splicing analysis, and Rluc knockdown) demonstrated that the SLC4A7 5'UTR possesses cap-independent translation activity enhanced by RPS5, whereas RPS5 regulates MAK16 translation without relying on this cap-independent element. Our data reveal a pro-oncogenic role of RPS5 in glioma progression and highlight its critical function in regulating translation. These findings provide new evidence supporting the central role of ribosome protein-induced translational dysregulation in cancer and offer innovative perspectives for developing molecular therapies targeting GBM.
    Keywords:  Glioblastoma multiforme; Internal ribosome entry site; Malignancy; Ribosomal protein S5; Solute carrier family 4 member 7; Translational dysregulation
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152279
  39. Sci Signal. 2026 May 05. 19(936): eaeb4530
    A Caenorhabditis elegans spatiotemporal proximity atlas reveals the MAPK p38 as a generator of phenotypic plasticity in vivo.
    Wang Yuan, Luke A Nunamaker, Yi M Weaver, Benjamin P Weaver.
      Phenotypic plasticity, the ability to change diverse traits without altering genomic information, is fundamental for organismal adaptations to changing environments. The mitogen-activated protein kinase (MAPK) pathway plays a key role in cellular adaptations to changing environments. To analyze the contributions of the MAPK p38 and its interaction partners to phenotypic plasticity in an animal, we established an in vivo proximity labeling proteomics method called ContinuumID. With this method, we built an atlas of PMK-1 physical interactors during development, in specific tissues, and during exposure to osmotic, ultraviolet, or oxidative stressors. We identified multiple stable and dynamic developmental stage-, tissue-, and stress-specific PMK-1 interactors. Phenotypic analyses of animals in which specific interactors were knocked down revealed considerable variability of diverse PMK-1-dependent outputs. These included target gene expression, survival under stress, lysosomal homeostasis during development, and neuronal integrity during aging. PMK-1 interactors exerted positive, negative, and neutral contributions to these outputs within and across functional pathways. Comparing developmental and stress-induced activation of PMK-1 and the regulatory functions of its interactors revealed that PMK-1 integrates the regulation of highly conserved protein synthesis and RNA processing pathways with that of rapidly changing signaling and metabolic adaptations to confer distinct survival advantages or disadvantages during stress.
    DOI:  https://doi.org/10.1126/scisignal.aeb4530
  40. FEBS Lett. 2026 May 07.
    AAA+ protein unfoldases-the Moirai of the proteome.
    Stavros Azinas, Marta Carroni.
      AAA+ ATPases safeguard proteostasis by harnessing ATP hydrolysis to unfold misfolded or damaged proteins. Depending on their specific structural motifs and partners, they either channel substrates to peptidases for degradation or disentangle aggregates for refolding. This conserved mechanism across all life domains relies on the conversion of chemical energy into mechanical force. Although structural, biochemical and single-molecule studies have provided valuable insights into ATP-driven unfolding, the precise threading mechanism remains unresolved. This review synthesises current knowledge on three classes of AAA+ unfoldases: (a) self-contained proteases with both ATPase and peptidase domains, (b) ATPases cooperating with separate peptidases and (c) ATPases dedicated to disaggregation and refolding without proteolysis. We discuss existing models, underline technological limitations and outline experimental approaches to address these challenges. Gaining a clearer picture of substrate threading will enhance our grasp of basic protein quality control and also enable modulation of proteostasis in eukaryotic cells, relevant to neurodegenerative diseases and antibiotic targeting of bacterial unfoldases. Like the mythological Moirai, AAA+ enzymes govern the fate of proteins, though their exact decision-making and handling of their protein substrates remains elusive.
    Keywords:  AAA+ unfoldases; ATP hydrolysis; cryo‐EM; single‐molecule techniques; substrate threading mechanism
    DOI:  https://doi.org/10.1002/1873-3468.70348
  41. Elife. 2026 May 08. pii: RP103427. [Epub ahead of print]14
    Mettl5 coordinates protein production and degradation of PERIOD to regulate sleep in Drosophila.
    Xiaoyu Wu, Xingzhuo Yang, Tiantian Fu, Yikang Rong, Juan Du.
      Sleep plays a critical role in animal physiology, primarily governed by the brain, and its disruption is prevalent in various brain disorders. Mettl5 is associated with intellectual disability (ID), which often includes sleep disturbances. However, the mechanism underlying these sleep disruptions in ID remains poorly understood. In this study, we investigated the sleep phenotypes resulting from Drosophila Mettl5 mutations. Rescue experiments revealed that Mettl5 functions predominantly within neurons and glia marked by Mettl5-Gal4 to regulate sleep. Previous work established that Mettl5 forms a complex with Trmt112 to influence rRNA methylation. Notably, a mutation in Trmt112 recapitulated these sleep disturbances, implicating translational regulation by the Mettl5/Trmt112 complex. Subsequent RNA-seq and Ribo-seq analyses of Mettl51bp mutants uncovered downstream effects, including altered expression of proteasome components and clock genes. Rescue experiments confirmed that the net increase in PERIOD protein underlies the sleep phenotype. This study illuminates the interplay between ribosome function, clock genes, and the proteasome in sleep regulation, highlighting the integrated roles of protein synthesis and degradation. These findings could potentially provide an example for in vivo study of rRNA methylation function, expand our understanding of protein homeostasis in sleep, and offer insights into the sleep phenotypes associated with ID.
    Keywords:  D. melanogaster; Mettl5; clock genes; genetics; genomics; proteasome; rRNA methyltransferase; sleep
    DOI:  https://doi.org/10.7554/eLife.103427
  42. Biomolecules. 2026 Apr 21. pii: 615. [Epub ahead of print]16(4):
    Cigarette Smoke Induces Canonical Stress Granule Formation in Human Bronchial Epithelial Cells in Reactive Oxygen Species- and PERK-Dependent Manners.
    Mousumi Bhowmik, Chenkun Zheng, Bisrat Bekele, Jessica Failler, Carlie Klatt, Souren Farimani, Bryant Jones, Chung-Chun Tyan, Asmahan Abu-Arish.
      Cigarette smoke (CS) is the primary risk factor for the development of chronic obstructive pulmonary disease (COPD). Investigating the impact of CS on human airway epithelium is important for understanding COPD development and combating its effects. While some studies show that long exposure to CS activates inflammasome formation in airway epithelium, leading to cytokines' maturation and release, its acute effect on inflammation regulation requires further elucidation. Due to the importance of acute cellular responses in modulating cell survival and controlling inflammatory outcomes, we examined the effect of acute cigarette smoke extract exposure on human bronchial epithelial cells. Due to the high reactive oxygen species content in CS, we hypothesize that acute CS exposure activates the integrated stress response (ISR) pathway leading to stress granules (SG) formation to facilitate oxidative stress resolution and promote cell survival. Immunostaining, fluorescence confocal imaging, quantitative analyses, and immunoblotting were performed to test our hypothesis. We report here that acute exposure to CS extract triggers canonical SG formation by activating the ISR pathway via the PERK/eIF2α arm in a reactive oxygen species-dependent manner. SG formation is abolished upon inhibiting PERK or eIF2α function, or by scavenging oxidants prior to smoke exposure. Characterizing SG formation in terms of measuring SG size and abundance and the sequestration of the SG marker G3BP1 reveals that SG formation is maximal at 15% CS extract exposure for 2 h and undergoes gradual disassembly at longer exposure times. This is closely dependent on cytoplasmic p-eIF2α levels. These results demonstrate that acute exposure to CS activates the protective ISR pathway to potentially reduce the detrimental effects of CS and promote stress resolution and cell survival.
    Keywords:  G3BP1; ISRIB; PERK; cigarette smoke extract; eIF2α; human bronchial epithelial cells; integrated stress response; quantitative immunofluorescence imaging; reactive oxygen species; stress granules
    DOI:  https://doi.org/10.3390/biom16040615
  43. J Biol Chem. 2026 May 06. pii: S0021-9258(26)01979-4. [Epub ahead of print] 113107
    An intricate functional relationship between NuA4 and Sfp1 regulates ribosome biogenesis in response to nutrient availability.
    Ke Xu, Stéphanie Bianco, Charles Joly Beauparlant, Valérie Côté, Lara Herrmann, Arnaud Droit, Michael Downey, Amine Nourani, Jacques Côté.
      Ribosome biogenesis is a crucial process requiring enormous transcriptional output. In budding yeast, the expression of 138 ribosomal protein (RP) genes and over 200 ribosome biogenesis (RiBi) genes is regulated by an intricate network of factors, including the nutrient-sensitive transcription activator Sfp1 and the NuA4 coactivator/acetyltransferase complex. Nutrient starvation or inhibition of TORC1 by rapamycin leads to repression of RP and RiBi genes, in part through blocking Sfp1 nuclear localization and NuA4-dependent chromatin acetylation. Here, we demonstrate that Sfp1 physically interacts with NuA4 in a TORC1-dependent manner. Our results indicate that Sfp1, along with NuA4, regulate the transcription of RiBi and RP genes via distinct mechanisms depending on promoter architectures. Sfp1 promotes histone acetylation at the promoters without affecting NuA4 recruitment. In contrast, NuA4 does impact Sfp1 binding but specifically at two classes of RP genes. Importantly, NuA4 acetylates Sfp1 at lysines 655 and 657, regulating its function. Cells expressing Sfp1 with acetyl-mimicking mutations exhibit increased expression of RiBi genes while RP genes remain stable. However, the same mutants lead to the loss of Sfp1 binding/activity at RiBi genes when cells are under non-optimal growth conditions. Mimicking constitutive acetylation of Sfp1 also limits the transcriptional burst of RP genes upon addition of glucose. Altogether, these results draw an intricate functional relationship between Sfp1 and NuA4 to control ribosome biogenesis, fine-tuning transcription output in different growth conditions.
    Keywords:  NuA4; Sfp1; acetylation; carbon source; chromatin; ribosomal proteins; ribosome biogenesis; transcription; yeast
    DOI:  https://doi.org/10.1016/j.jbc.2026.113107
  44. Trends Biochem Sci. 2026 May 01. pii: S0968-0004(26)00106-4. [Epub ahead of print]
    Thermospermine drives dual-action ribosomes to shape plant xylem development.
    Hsin-Yen Larry Wu, Polly Yingshan Hsu.
      The formation of xylem vessels depends on a balance between transcription factors SACLs and LHW, whose translation is controlled by thermospermine. A recent study shows that a conserved rRNA methylation by OVERACHIEVER enables thermospermine binding, allowing ribosomes to oppositely regulate SACL and LHW translation to direct plant xylem cell fate.
    Keywords:  cell-fate decision; polyamine; rRNA methylation; translational control; xylem development
    DOI:  https://doi.org/10.1016/j.tibs.2026.04.006
  45. NAR Genom Bioinform. 2026 Jun;8(2): lqag044
    RNAStructuromeDB: a transcriptome-wide database of predicted RNA secondary structures with integrated APIs for functional annotation and RNA-targeted drug discovery.
    Abdelraouf O Dapour, Jacopo Manigrasso, Warren B Rouse, Giuseppina La Sala, Miles V Aronnax, Leonardo De Maria, Russell S Hamilton, Sergio Martinez Cuesta, Anders Hogner, Walter N Moss.
      RNA structure critically governs biological function in both physiological and pathological contexts, making high-resolution structural maps essential for RNA-targeted therapeutics. Yet, despite recent advances, well-validated structural targets for drug design remain limited. To help bridge this gap, we generated the first genome-scale map of the human RNA structurome by applying ScanFold to >230 000 annotated human pre-mRNA transcripts, identifying sequences likely evolved to form highly stable and functional secondary structures. We also performed a global analysis of regions with z-scores ≤ -2 and statistically characterized their two-dimensional folding patterns. In addition, we developed the RNA-Annotator Pipeline to integrate 20 diverse biological annotations, such as tissue-specific expression and protein interactions, with the structural data. Our results reveal local folding propensities and unusually stable structures with high-confidence architectures, providing insights for prioritizing RNA targets and guiding therapeutic design, including antisense oligonucleotides and small molecules. All ScanFold results are publicly available through RNAStructuromeDB. Using the RNA-Annotator Pipeline, analysis of SMN1 and SMN2 pre-mRNAs showed that a single C-to-T transition in SMN2 induces structural rearrangements that disrupt a critical splicing enhancer. This toolkit establishes an integrated workflow that enables researchers to explore RNA structure-function relationships and accelerate advances in RNA-targeted drug discovery and RNA biology.
    DOI:  https://doi.org/10.1093/nargab/lqag044
  46. Life Sci Alliance. 2026 Jul;pii: e202503536. [Epub ahead of print]9(7):
    A microRNA generated via lysosomal processing of ribosomal RNA suppresses proinflammatory responses.
    Dan Michael, Ester Feldmesser, K Shanmugha Rajan, Yoav Lubelsky, Anat Bashan, Alexandros Damalas, Shiri Ben Zvi, Aya Friedberg, Netta Eitan, Shachar Erez, Ada Yonath, Igor Ulitsky, Moshe Oren.
      ER stress underlies numerous severe pathologies. We have metabolically perturbed normal fibroblasts to study the biological roles of microRNAs (miRs) under mild and extended ER stress. We now report that miR-4488 quenches inflammation-associated gene expression in such metabolically perturbed cells. Remarkably, generation of miR-4488 is Drosha-independent. Furthermore, we define miR-4488 as a noncanonical miRNA derived from the expansion segment ES7L of the 28S ribosomal RNA. Moreover, its generation involves the autophagy-lysosome route and is inhibited when this pathway is blocked, thus unveiling an anti-inflammatory role for ribosomal RNA and lysosomes, engaged at the onset of stress. Mechanistically, miR-4488 suppresses the expression of NFKB2 and RELB, whose mRNAs specifically associate with miR-4488 exclusively upon stress. This selectivity suggests that miR-4488 may bear promise for treating mild ER stress-associated diseases.
    DOI:  https://doi.org/10.26508/lsa.202503536
  47. Free Radic Biol Med. 2026 May 06. pii: S0891-5849(26)00745-8. [Epub ahead of print]
    Salubrinal-activated integrated stress response protects against doxorubicin-induced cardiotoxicity via activating transcription factor 4-mediated antioxidant defense and glutathione homeostasis.
    Sheng-Fan Wang, Hsuan-Yu Chou, Pei-Hsun Liu, Hsing-Hui Su, Giun-Yi Hung, Chian-Ying Chou, Ling-Ming Tseng, Yuh-Chiang Shen, Jiin-Cherng Yen, Shiang-Suo Huang, Hsin-Chen Lee.
      Doxorubicin is an effective chemotherapeutic agent; however, its use is limited by cardiotoxicity. Mitochondrial dysfunction is a central driver of doxorubicin-mediated cardiotoxicity. The role of the integrated stress response (ISR), a mitochondria-to-nucleus signaling pathway and crucial cellular defense mechanism in doxorubicin-induced cardiotoxicity, remains unclear. We investigated the pharmacological ISR activator salubrinal, a selective inhibitor of eukaryotic initiation factor 2α dephosphorylation with potential cardioprotective properties, to elucidate the molecular mechanisms underlying ISR-mediated cardioprotection in H9c2 cardiomyocytes, C57BL/6 mice, and HL-1 cell models. Doxorubicin disrupts ISR signaling, whereas salubrinal alleviates cardiotoxicity by activating transcription factor 4 (ATF4, a central ISR hub)-dependent pathways that suppress doxorubicin-induced apoptosis and preserve mitochondrial metabolism. The cystine/glutamate antiporter xCT, essential for glutathione (GSH) homeostasis, and growth differentiation factor 15 (GDF15), a mitochondrial stress-induced mitokine and potential biomarker of doxorubicin cardiotoxicity, are both regulated by ATF4. Mechanistically, we found that salubrinal contributes to cardioprotection against doxorubicin by enhancing the GSH-based antioxidant capacity via the ATF4-dependent GDF15-xCT axis. Further analysis of ATF4-associated GSH regulatory pathways revealed that enzymes involved in serine metabolism and glutathione peroxidase 4, a critical enzyme in GSH utilization that is upregulated by ATF4-mediated heat shock 70 kDa protein 5 and cystathionine gamma-lyase, contribute to the cardioprotective effects of salubrinal against doxorubicin-induced oxidative stress. Our findings highlight the ISR as a vital survival mechanism in cardiomyocytes exposed to doxorubicin. Regulating antioxidant defenses through enhanced GSH homeostasis and ISR activation, particularly via pharmacological agents such as salubrinal, may offer a promising therapeutic strategy for mitigating doxorubicin-induced cardiotoxicity.
    Keywords:  cardiotoxicity; doxorubicin; glutathione; integrated stress response; mitochondria; salubrinal
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.281
  48. Plants (Basel). 2026 Apr 20. pii: 1262. [Epub ahead of print]15(8):
    Functional Analysis of MADS-Box Gene Family in Stress Response and Prospects of Breeding Application.
    Jiaxuan Wang, Hongying Wang, Mengyao Li, Yujie Chen, Bingyan Song, Yingying Li, Xuhui Meng, Jie Li, Wenting Lu, Yi Gao, Yao Zhang, Aoxue Wang.
      The MADS-box family is a multifunctional family of transcription factors characterized by the presence of a unique MADS domain, which plays an important part in regulating essential biological processes, including metabolic synthesis and the stress response. In this review, we analyze the structural features and classification of MADS-box proteins, then summarize the functions of the MADS-box family in the stress response. The MADS-box family can directly regulate downstream functional genes by binding to the CArG-box in the promoters of target genes, thereby influencing growth, development, and stress responses. Also, MADS-box transcription factors can form protein complexes with both MADS-box proteins and other types of transcription factors and chromatin regulatory proteins to modulate the chromatin state or transcriptional activation. Furthermore, they can regulate plant physiological responses by facilitating the synthesis of essential signaling molecules, including hormones and non-coding RNA. Finally, we discuss the potential of the MADS-box family in crop molecular breeding, offering a novel approach for developing high-yield and stress-resistant cultivars for solving global food security and climate change challenges.
    Keywords:  MADS-box transcription factors; molecular breeding; stress
    DOI:  https://doi.org/10.3390/plants15081262
  49. Biomolecules. 2026 Apr 13. pii: 574. [Epub ahead of print]16(4):
    Polyamine Metabolism and the DHPS/eIF5A Hypusination Axis: From Metabolic Reprogramming to a Therapeutic Achilles' Heel in Melanoma.
    Kai-Li Liu, Shuo Zhang, Feng-Shuo Li, Min-Jin Chen, Yuan-Yuan Chen, Ning Zhang, Kai Wang.
      The polyamine metabolic pathway, an evolutionarily conserved nexus integrating nutrient sensing, translation control, and cellular proliferation, is fundamentally rewired in cancer. Melanoma, a malignancy of melanocytes notorious for its metastatic propensity and therapy resistance, exhibits a profound dependency on this pathway, extending beyond mere polyamine abundance to the specialized function of their derivative, hypusine. This review synthesizes cutting-edge insights into the deoxyhypusine synthase (DHPS)/eukaryotic initiation factor 5A (eIF5A) hypusination circuit as a critical amplifier of oncogenic signaling in melanoma. We dissect its role as a translational rheostat for pro-tumorigenic proteomes, a driver of phenotypic plasticity underpinning invasion and vasculogenic mimicry, and a modulator of the immunosuppressive tumor microenvironment. Moving beyond the classical inhibitor GC7, we explore the emergence of novel allosteric DHPS inhibitors with compelling preclinical efficacy. Finally, we propose a paradigm shift: targeting the DHPS/eIF5A axis represents a strategy to disrupt the "non-oncogene addiction" of melanoma-its reliance on hyperactive translation and adaptive survival mechanisms-offering a promising avenue alongside targeted therapies and immunotherapies.
    Keywords:  deoxyhypusine synthase (DHPS); eukaryotic initiation factor 5A (eIF5A); hypusination; melanoma metastasis; polyamine metabolism
    DOI:  https://doi.org/10.3390/biom16040574
  50. Mol Biol Rep. 2026 May 05. pii: 711. [Epub ahead of print]53(1):
    Rational construction of rpsL or/and rpoB merodiploids affects biosynthesis of secondary metabolite in Streptomyces.
    Chen Lu, Xiaoyu Pan, Shiying Yang, Jinyao Zhang, Yujie Jiang, Yongyong Zhang, Andreas Bechthold, Zheng Ma.
       BACKGROUND: Ribosome engineering technology typically involves resistance screening of streptomycin and rifampin to introduce point mutations in genes ribosomal protein S12 (rpsL) or RNA polymerase (rpoB), thereby enhancing the synthesis level of secondary metabolites in Streptomyces. Currently, directly introducing copies of genes rpsL and rpoB carrying "beneficial mutations" to construct diploids has become a more rapid and efficient method for obtaining high-yielding Streptomyces strains.
    METHODS AND RESULTS: We directly introduced these beneficial mutations (rpsL: K88E/P91S; rpoB: S433L/H437Y/R440C) to construct single or combined merodiploids. Introducing rpsL-K88E promoted secondary metabolite biosynthesis in both strains S. coelicolor M145 and S. diastatochromogenes 1628, notably increasing tetramycin A production by 66% in 1628-rpsL-K88E. However, rpsL-P91S yielded no significant positive effects. Regarding rpoB, the M145-rpoB-H437Y strain showed a modest enhancement, with actinorhodin and undecylprodigiosin yields increasing by 20% and 22%. In S. diastatochromogenes 1628, introducing rpoB-H437Y, rpoB-R440C and rpoB-S433L promoted the synthesis of toyocamycin and tetraene macrolides to varying degrees.
    CONCLUSIONS: Constructing a diploid by directly introducing the rpsL and rpoB genes carrying "beneficial mutations" is an effective strategy to enhance the synthesis level of secondary metabolites, whether for the model strain S. coelicolor M145 or the industrial strain S. diastatochromogenes 1628.
    Keywords:   RpoB ; RpsL ; Streptomyces coelicolor M145; Streptomyces diastatochromogenes 1628; Ribosome engineering
    DOI:  https://doi.org/10.1007/s11033-026-11871-2
  51. bioRxiv. 2026 Apr 27. pii: 2025.02.04.636058. [Epub ahead of print]
    Stress Granule Sequestration of CCR4-NOT Promotes Poly(A) Lengthening of Stress-Survival Transcripts.
    Yi-Cheng Tsai, Hiroyuki Uechi, Sean R Millar, Eileigh Kadijk, Alon Minkovich, John Paul Tsu Ouyang, Karl J Schreiber, Jie Qi Huang, Carina A Lyons, Vesal Kasmaeifar, Zhixin Zhang, Rico Barsacchi, Claudia Möbius, Antje Janosch, Jonathan C Savage, Olivia S Rissland, Hannes Röst, Anthony A Hyman, Ji-Young Youn.
      Cells adapt to stress by rewiring their post-transcriptional gene regulation. Stress granules-biomolecular condensates composed of polyadenylated RNAs and RNA-binding proteins-are implicated in this process, yet their precise functional roles remain debated. To address this, we mapped the dynamic proteomic landscapes of stress granules formed under oxidative and hyperosmotic stress using multi-bait BioID proximity profiling coupled with quantitative mass spectrometry. This analysis revealed context-specific remodeling of proximal interaction networks and identified a conserved, stress-dependent shift in association with the CCR4-NOT deadenylase complex. A complementary genome-wide chemical genetic screen further implicated CCR4-NOT in stress granule biology, showing that reduced CCR4-NOT activity bypassed lipoamide-mediated inhibition of stress granule assembly. Microscopy showed sequestration of the CCR4-NOT complex into stress granules, and global transcriptomic analyses revealed that this relocalization promotes poly(A) tail lengthening and increased abundance of stress-induced survival transcripts. Together, integration of proteomics, chemical genetics, and transcriptomics uncovers a spatial mechanism by which stress granule assembly promotes cellular adaptation to stress through sequestration of CCR4-NOT from the cytosol and consequent remodeling of post-transcriptional regulation.
    DOI:  https://doi.org/10.1101/2025.02.04.636058
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