bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–06–07
forty-nine papers selected by
Cédric Chaveroux, CNRS
  1. Non-enzymatic RNA Glycation is a Metabolic Sensor of Cellular Stress.
  2. The crucial role of m6A methylation modification in nasopharyngeal carcinoma.
  3. Lost in translation: interferon-stimulated genes targeting flavivirus protein synthesis.
  4. NudC moonlights in ribosome biogenesis and homeostasis in polyploid cells of Drosophila melanogaster.
  5. Mapping the rRNA methylome reveals contributions of methyltransferases to ribosome function and antibiotic sensitivity.
  6. Endothelial cell RpL17-dependent translational control mediates intima-media thickening in response to disturbed flow.
  7. Ago1 is required for the regulation of mitochondrial translation under heat stress in S. pombe.
  8. Genomic insights into the tunicamycin-induced endoplasmic reticulum stress response in peripheral blood mononuclear cells: A comprehensive RNA sequencing analysis.
  9. Ribosomal protein eL22 contributes to the assembly of 60S ribosomal subunits in Saccharomyces cerevisiae.
  10. Mapping the interactome of human tRNA methyltransferase TRMT1 using dual proximity labeling.
  11. Functional assignments of the ubiquitination sites K62 and K230 of the human ribosomal protein uS3 (RPS3).
  12. Stress-induced ribosome degradation in Bacillus subtilis is mediated by the RNase Y-specificity complex.
  13. Translation as a regulatory hub for secondary metabolism in Streptomyces spp.
  14. Interplay of the ribosome A and CAR sites.
  15. Divergent RNA structures support accurate splicing of the SF3B1-sensitive MAP3K7 intron.
  16. Brief Investigation: Investigating the role of phosphodiesterase Pde2 in coordinating the yeast Environmental Stress Response.
  17. The Role of Stress Granules in Cardiovascular Diseases.
  18. GPSM2 Promotes Pancreatic Cancer Progression Through METTL3-Mediated m6A Modification of YAP1 mRNA.
  19. Direct RNA Sequencing reveals epitranscriptomic regulation of brain cells and Alzheimer's Disease pathology.
  20. TRMT6/61A-mediated m 1 A methylation facilitates human pre-tRNA maturation and prevents surveillance by XRN2.
  21. A novel ICP-MS strategy identifies arsenite as an inhibitor of selenocysteine-tRNASec charging.
  22. Consequences of defective mitochondrial protein import: From targeting signals to pathology.
  23. Nascent protein retention at polysomes reduces kinetic barriers to self-assembly.
  24. Structural studies of nedicistrovirus IRES-driven, initiation factor-independent translation shed light on key steps of eukaryotic translation elongation.
  25. Endoplasmic Reticulum Stress as a Stage-Dependent Regulatory Hub in Rheumatoid Arthritis.
  26. Hyperosmotic stress-induced redistribution of pre-mRNA cleavage factor I subunits is associated with shifts in alternative polyadenylation.
  27. Muscleblind-like proteins dimerize by forming disulfide bonds to regulate alternative splicing and pathogenic RNA foci formation.
  28. Ribosome impairment, tau alternative splicing, and stress granules: a convergent axis of neuronal vulnerability driving Alzheimer's disease.
  29. SnoRNA Expression and RNA 2'-O-Methylation in Drosophila melanogaster S2 Cells.
  30. An RNA Language Model trained on sequence alone reveals the structural logic of Internal Ribosome Entry Sites.
  31. rDNA breaks activate dsRNA pattern recognition through sense-antisense transcription.
  32. FTO in cardiovascular diseases: mechanisms, context dependence, and translational opportunities.
  33. HPAIV-induced heat shock protein expression in chickens and its potential NF-κB-mediated transcriptional regulation.
  34. Elp3 uses a conserved molecular tunnel to transport acetate between distant active sites and catalyze tRNA wobble base modification.
  35. Cell-type-resolved RNP topologies reveal dynamic structural mechanisms of splicing and therapeutic targets.
  36. Metabolically Induced Intestinal Inflammation: The Role of ER Stress and Autophagy in a Porcine Model of Diabetes.
  37. Molecular Chaperone Networks in Plants: Maintaining Proteostasis and Enhancing Stress Resilience for Crop Improvement.
  38. Stress Granules and Tau Pathology in Alzheimer's Disease: A Scoping Review of Bidirectional Interactions, Liquid-Liquid Phase Separation, and Proteostatic Consequences.
  39. Oncofetal RNA-binding proteins of IGF2BP family suppress IRF-3 and NF-kB dependent transcription downstream of cytosolic RNA sensors.
  40. FBXL21 regulates diurnal proteostasis and stress response by targeting DNAJB6 and client proteins.
  41. METTL3-Mediated m6A Modification of FYN: Regulating Tumor-Associated Endothelial Cells in Colorectal Cancer Progression.
  42. Cytosolic and ER-associated ribosomes share rRNA 2'-O-methylation landscapes across human cell types.
  43. Defining cell surface and glycosylated RNAs.
  44. Heat Shock Protein 90: From Molecular Chaperone Function to Therapeutic Targeting in Malignancies.
  45. RBM46 promotes meiotic initiation during oogenesis.
  46. Single-Cell Translation and Apoptosis Profiling to Define Human CD34 + Cell Response to Specific Factors.
  47. Cryo-EM reveals multiple mechanisms of ribosome inhibition by doxycycline.
  48. Deep learning of functional perturbations from condensate morphology.
  49. Neutrophils repurpose the nucleolus as a cytokine reservoir and secretory organelle.
  1. bioRxiv. 2026 May 19. pii: 2026.05.18.725511. [Epub ahead of print]
    Non-enzymatic RNA Glycation is a Metabolic Sensor of Cellular Stress.
    Anna Knörlein, Kaila Nishikawa, Naoya Kitamura, Reena Kumari, Shino Murakami, Ankita Shrivastava, Malina Doynova, Nicolae Ciobu, Nicole Walker, Xiaohan Mei, Abdul Vehab Dozic, Jahan Rahman, Yang Xiao, Chiara Evans, Xuejing Yang, Michael G Kharas, Omar Abdel-Wahab, Francois Fuks, Kamini Singh, Samie Jaffrey, Viraj R Sanghvi, James J Galligan, Yael David.
      Non-enzymatic RNA modifications expand the epitranscriptome, encoding a rapid and chemistry-driven response to cellular stress. While methylglyoxal, a reactive glycolytic byproduct of metabolic stress, has been shown to modify proteins and DNA, its impact on RNA has remained unexplored. Here, we identify mRNA as a dynamic substrate of MGO, whose modification is actively regulated by DJ-1 and the glyoxalase detoxification system. We show that mRNA glycation impairs translation and engages both the integrated stress response and the ribotoxic stress pathway, culminating in compromised pancreatic β-cell function and reduced insulin secretion. Notably, this phenotype is alleviated by the frontline antihyperglycemic agent metformin. Together, our findings position mRNA as a direct sensor of metabolic stress and establish RNA glycation as a mechanistic link between glycolytic imbalance, translational stress and disease.
    DOI:  https://doi.org/10.64898/2026.05.18.725511
  2. Discov Oncol. 2026 May 31.
    The crucial role of m6A methylation modification in nasopharyngeal carcinoma.
    Lijie Jin, Jianxin Song.
      Nasopharyngeal carcinoma (NPC) is an epithelial malignancy originating from the nasopharyngeal mucosa and represents one of the most prevalent malignant tumors globally. RNA modifications function as a key epigenetic regulatory mechanism, governing post-transcriptional gene regulation. Among these, N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic mRNA and plays a pivotal role in regulating RNA transcription, splicing, stability, and translation. Extensive research has demonstrated that m6A modification regulates the expression of numerous oncogenes and tumor suppressor genes and is closely associated with cancer initiation and progression. Notably, regulators of m6A methylation exhibit aberrant expression in NPC tissues, and their dysregulation is closely linked to tumor development and therapeutic resistance. This evidence suggests their potential as molecular targets for NPC diagnosis and treatment. This review examines the pivotal role of m6A in NPC, encompassing its influence on cell proliferation, migration, invasion, and resistance to radiotherapy and chemotherapy. Furthermore, it explores recent advances in the application of m6A for NPC diagnosis and molecularly targeted therapy, and summarises current techniques for detecting m6A modifications.
    Keywords:  Biological function; Drug resistance; Nasopharyngeal carcinoma; Radiotherapy resistance; m6A
    DOI:  https://doi.org/10.1007/s12672-026-04718-6
  3. J Virol. 2026 Jun 04. e0030326
    Lost in translation: interferon-stimulated genes targeting flavivirus protein synthesis.
    Marion Cannac, Jim Zoladek, Sébastien Nisole.
      Flaviviruses are positive-sense RNA viruses that rely entirely on host translation machinery to express their genome, making protein synthesis a central point of vulnerability. Interferon-stimulated genes (ISGs) exploit this dependence through diverse and mechanistically distinct strategies. PKR and IFIT proteins interfere primarily with translation initiation by targeting initiation factors or cap recognition, whereas SLFN11 and SAMD9L impair elongation through codon- and tRNA-dependent mechanisms. In parallel, ZAP, SHFL, and ISG20 inhibit translation by excluding viral RNAs from ribosomes or promoting their degradation. These antiviral activities highlight that ISG-mediated restriction is often highly selective, targeting viral RNAs on features such as cap structure, nucleotide composition, codon usage, and RNA folding. As a result, translation emerges as a central interface of host-virus conflict, where subtle differences between viral and cellular mRNAs can be exploited to achieve potent antiviral effects while preserving host protein synthesis. This minireview highlights recent advances in the identification and characterization of ISGs that restrict flavivirus protein synthesis and integrates them into a unified framework based on their primary mechanism of action. Emphasizing how host defenses target multiple stages of translation provides a conceptual basis for understanding how innate immunity controls flavivirus replication and highlights viral translation as a promising target for selective antiviral strategies.
    Keywords:  Orthoflavivirus; RNA structure; innate immunity; interferon-stimulated genes (ISGs); restriction factors; ribosome; translation control; viral RNA
    DOI:  https://doi.org/10.1128/jvi.00303-26
  4. Open Biol. 2026 Jun 03. pii: 260066. [Epub ahead of print]16(6):
    NudC moonlights in ribosome biogenesis and homeostasis in polyploid cells of Drosophila melanogaster.
    Duoduo Shi, Yuko Shimada-Niwa, Naoki Okamoto, Akira Nakamura, Yuya Ohhara, Yuichi Shichino, Shintaro Iwasaki, Wei Sun, Ryusuke Niwa.
      Ribosomes, the cellular machinery responsible for protein synthesis, are fundamental across all kingdoms of life. Disruption of ribosome biogenesis (RiBi) can cause severe ribosomopathies, underscoring the need for precise regulatory mechanisms. In this study, we identified a role for the gene nuclear distribution C, dynein complex regulator (NudC) in RiBi within polyploid cells of Drosophila melanogaster larvae. Depletion of NudC in polyploid salivary gland cells led to a significant reduction in ribosome abundance, accompanied by the loss of ribosome-binding sites on the rough endoplasmic reticulum and impaired translation. These defects are linked to decreased ribosomal RNA levels. Notably, NudC knockdown also triggered a homeostatic response, characterized by increased transcription and translation of ribosome biogenesis factors and ribosomal proteins. This response is similar to that observed in cells with defective ribosomal activity, suggesting that the ribosomal impairment triggers transcriptional feedback to maintain ribosome function. Meanwhile, NudC-deficient cells exhibited chromosome abnormalities, JNK signalling activation and autophagy-resembling defects from ribosome dysfunction. Finally, our findings suggest that the role of NudC in RiBi is independent of its established function in dynein regulation, indicating its moonlighting role in RiBi. Together, these results uncover a new, fundamental function for NudC in maintaining RiBi and homeostasis in polyploid cells.
    Keywords:   Drosophila melanogaster ; NudC; homeostasis; nucleolus; polyploid cells; ribosome biogenesis; salivary gland; stress response
    DOI:  https://doi.org/10.1098/rsob.260066
  5. bioRxiv. 2026 May 27. pii: 2026.05.25.727669. [Epub ahead of print]
    Mapping the rRNA methylome reveals contributions of methyltransferases to ribosome function and antibiotic sensitivity.
    Jennie L Hibma, Kaley M Simcox, Lia M Munson, Lauren E Barnes, Kristin S Koutmou, Lyle A Simmons.
      Ribosomal RNA (rRNA) folds into a complex structure used as the macromolecular core for protein synthesis. Chemical modification of rRNA contributes to ribosome structure, function, and susceptibility to antibiotics. Despite their importance, the enzymes responsible for specific rRNA modifications remain unknown in most species. In this work, we integrate genetics and biochemistry with sequencing and mass spectrometry to uncover enzymes responsible for rRNA methylation events in Bacillus subtilis . We characterize 17 enzymes responsible for 20 methylation modifications on the 16S and 23S rRNAs, 11 of which are encoded by previously uncharacterized genes. For each rRNA methyltransferase, we define the modification identity, location, and we determine the impact of loss of cognate rRNA methylation on ribosome biogenesis and antibiotic sensitivity. Our findings demonstrate that loss of nearly half of the 17 genes studied results in alterations to ribosome assembly or antibiotic sensitivity underscoring the importance of chemical modifications to ribosome function.
    DOI:  https://doi.org/10.64898/2026.05.25.727669
  6. bioRxiv. 2026 May 25. pii: 2026.05.21.726977. [Epub ahead of print]
    Endothelial cell RpL17-dependent translational control mediates intima-media thickening in response to disturbed flow.
    Mary Wines-Samuelson, Sayantani Chowdhury, Sharon Senchanthisai, Michal Shaposhnikov, Mark Sowden, Bradford C Berk.
       Background: Carotid intima-media thickening (IMT) is a major risk factor for cardiovascular disease (CVD). The large ribosomal subunit protein 17 (Rpl17) was recently reported as a CVD-associated gene; however, ribosomal mutations generally are not associated with vascular dysfunction. We have created a novel genetic model of decreased RpL17 in endothelial cells (EC) to determine how changes in endothelial ribosome expression cause IMT.
    Methods: EC-restricted RpL17 heterozygous mice (Cdh5-Cre; RpL17 fl/wt , or Rpl17-Het), were generated and subjected to sham or partial carotid ligation (PCL) surgery of the left artery to induce acute disturbed (d)-flow in vivo . Carotids were harvested on day 14 for quantitative tissue immunostaining. Purified mouse and human EC in vitro were exposed to steady (s)-flow or d-flow using cone viscometry, and collected for flow cytometry, protein expression, electron microscopy, or purification of ribosomes. Human carotid samples from healthy and endarterectomy patients were used for tissue analysis.
    Results: Carotids from RpL17-Het mice with PCL-induced d-flow showed increased IMT relative to RpL17-WT controls. In addition, RpL17 protein levels were decreased in regions of d-flow compared to s-flow. Increased levels of ER stress markers were observed by carotid immunostaining, as well as activation of the integrated stress response (ISR) in RpL17-Het EC. Analysis of mRNAs bound to polysomes vs. monosomes in EC-RpL17-Het revealed increased translational efficiency of key regulators of glycolysis, redox, inflammation, matrix, and endothelial-to-mesenchymal transition (EndMT). Metabolic profiling by Seahorse assay showed enhanced anaerobic glycolysis and decreased oxidative respiration in RpL17-Het EC, consistent with the translational efficiency data. Immunostaining of carotids identified upregulated EC inflammation and EndMT.
    Conclusions: Our data support RpL17 as a key mediator of EC phenotypic modulation that causes IMT in response to d-flow. We show a novel pathway for d-flow-mediated IMT: endoplasmic reticulum stress and activation of the ISR. These changes alter translational efficiency and reprogram EC cell cycle, metabolism, and redox state in the presence of d-flow to cause IMT, a precursor to cardiovascular pathology.
    DOI:  https://doi.org/10.64898/2026.05.21.726977
  7. J Biol Chem. 2026 Jun 04. pii: S0021-9258(26)02107-1. [Epub ahead of print] 113235
    Ago1 is required for the regulation of mitochondrial translation under heat stress in S. pombe.
    Mengling Yu, Yuanqi Xu, Yijing Lu, Minjie Li, Yucheng Yao, Gang Feng, Ying Huang, Jinjie Shang.
      Mitochondrial protein synthesis is a critical component of OXPHOS complexes, vital for both mammals and Schizosaccharomyces pombe. In our study, we investigated the effect of heat stress on mitochondria, analyzed the mitochondrial proteome and found that during heat stress, the translation of all mtDNA-encoded transcripts was impaired, leading to a reduction in the steady-state levels of mtDNA-encoded proteins, suggesting that heat stress plays a general role in mitochondrial protein synthesis. We also found that heat stress affects the association of mitochondrial translation initiation factors to mitoribosomal small subunits. Interestingly, ago1 deletion compensates for the heat-induced disruption of the interaction between mitochondrial translation initiation factor and mitoribosomes, leading to partial recovery of both translation and steady-state levels of mtDNA-encoded proteins in S. pombe. Under heat stress, Ago1 accumulates in the mitochondrial matrix. C-terminal truncation ablates this localization and abolishes rescue of translational suppression, confirming mitochondrial targeting is essential for regulatory function. Furthermore, our data demonstrate that Ago1's small RNA-loading related N-terminal domain is required for heat-induced translational suppression and that Ago1 physically engages with mitochondrial RNAs, collectively indicating potential RNA interference (RNAi) activity within mitochondria. These findings provide insight into the regulation of mitochondrial protein synthesis in heat stress.
    Keywords:  Heat stress; Mitochondria; Mitochondrial protein synthesis; Mitochondrial translation; Schizosaccharomyces pombe
    DOI:  https://doi.org/10.1016/j.jbc.2026.113235
  8. Biochem Biophys Rep. 2026 Jun;46 102640
    Genomic insights into the tunicamycin-induced endoplasmic reticulum stress response in peripheral blood mononuclear cells: A comprehensive RNA sequencing analysis.
    Laura S Mahl, Axel H Meyer.
      Tunicamycin induces endoplasmic reticulum (ER) stress by inhibiting N-glycosylation of newly synthesized proteins, leading to accumulation of misfolded proteins in the ER. This activates the unfolded protein response (UPR), a conserved adaptive pathway aimed at restoring proteostasis. A key mediator of this response is the kinase PERK which activates a signal cascade that leads to a global reduction in translation, while selectively enhancing the expression of stress-associated genes. This PERK-mediated response also constitutes a major arm of the integrated stress response (ISR). Under persistent ER stress, these response pathways may trigger pro-apoptotic programs in addition to adaptive responses. In this study, we used next-generation RNA sequencing to profile transcriptional changes in peripheral blood mononuclear cells (PBMCs) after 24 h of tunicamycin exposure, alone or with the PERK inhibitor GSK2606414 or the eIF2B activator ISRIB, to assess stress responses at distinct regulatory points within the PERK-ISR pathway. Key findings were validated by qRT-PCR, and pathway enrichment analysis was performed using the Gene Ontology Resource and the Reactome database. ER stress altered gene expression, with 4.80% of genes upregulated and 12.67% downregulated. GSK2606414 suppressed a broader subset of tunicamycin-induced genes than ISRIB. However, both inhibitors effectively reversed upregulation of the top two stress-responsive genes, TNC and WNT5A. Pathway enrichment analysis revealed overrepresentation of pathways related to ER stress responses, unfolded protein homeostasis, ER chaperone complex assembly, amino acid biosynthesis and interconversion, and aminoacyl-tRNA synthetase-mediated protein translation. These findings provide mechanistic insights into chronic ER stress in PBMCs and identify WNT5A and TNC as candidate biomarkers, pending further validation.
    Keywords:  ER stress; ISR; PBMCs; PERK; Transcriptomics; Tunicamycin; UPR; eIF2α
    DOI:  https://doi.org/10.1016/j.bbrep.2026.102640
  9. bioRxiv. 2026 May 22. pii: 2026.05.20.726491. [Epub ahead of print]
    Ribosomal protein eL22 contributes to the assembly of 60S ribosomal subunits in Saccharomyces cerevisiae.
    José Fernández-Fernández, Sara Martín-Villanueva, Taylor N Ayers, Carla V Galmozzi, John L Woolford, Jesús de la Cruz.
      Ribosome biogenesis is a highly coordinated pathway that involves the assembly of ribosomal RNAs (rRNAs) with ribosomal proteins (r-proteins) to generate functional ribosomal subunits (r-subunits). The Saccharomyces cerevisiae (yeast) large 60S r-subunit consists of three rRNA molecules and 46 r-proteins. The contributions of nearly all r-proteins of the yeast large r-subunit have been characterized; however, a few non-essential proteins remain poorly understood. Although non-essential, human eL22 has been identified as a key player in p53 regulation during ribosomal stress and as a highly mutated target in cancers. Despite this function, the role of eL22 in ribosome maturation is still ill-defined. In this study, we characterized yeast eL22 r-protein. Our results show that eL22 assembles into intermediate nucleolar pre-60S ribosomal particles. Loss of eL22 impairs cell growth and reduces 60S r-subunit accumulation, phenotypes that are exacerbated at low temperatures. Analysis of pre-rRNA processing by pulse-chase labeling, northern blot hybridization, and primer extension reveals a defect in 27S pre-rRNA maturation, specifically at the level of 27SB pre-rRNA processing. Consequently, nuclear export of eL22-deficient pre-60S particles is mildly impaired. Furthermore, we identify genetic interactions between eL22 and neighboring r-proteins, eL38 and eL31. We conclude that eL22 assembly is required for optimal pre-60S maturation during middle nucleolar stages, particularly at low temperatures, a function likely supported by the cooperative action of other r-proteins associated with common elements of 25S rRNA.
    Highlights: We have studied the role of r-protein eL22 in yeast ribosome assembly.eL22 is required for 60S ribosomal subunit production.The absence of eL22 is critical at low temperatures.eL22 is important for 27SB pre-rRNA processing and nuclear export of pre-ribosomes.eL22 functionally interacts with r-proteins eL38 and eL31 in domain III of 25S rRNA.
    DOI:  https://doi.org/10.64898/2026.05.20.726491
  10. bioRxiv. 2026 May 19. pii: 2026.05.18.725941. [Epub ahead of print]
    Mapping the interactome of human tRNA methyltransferase TRMT1 using dual proximity labeling.
    Angel D'Oliviera, Sophie Olson, Harrison Bernhard, Yanbao Yu, Jeffrey S Mugridge.
      Transfer RNA methyltransferase 1 (TRMT1) installs N2-methylguanosine and N2,N2-dimethylguanosine modifications at position 26 of mammalian tRNAs, supporting tRNA structure, translation, and cellular response to redox stress. However, the local environment and interactome of TRMT1 in the cell is poorly defined. Here, we use APEX2-based proximity labeling of the N- and C-terminus of TRMT1, coupled with label-free quantitative proteomics to map candidate TRMT1-proximal proteins in HEK293T cells. Mass spectrometry data was acquired using both data-independent acquisition (DIA) and data-dependent acquisition (DDA) methods, and it was found that DIA substantially increased proximity proteome coverage, reproducibility, and the number of significantly enriched candidate hits compared to the DDA method. N- and C-terminal APEX2-TRMT1 constructs captured largely overlapping proteomes, suggesting the dual-labeling strategy provides a robust map of proximal proteins. Analysis of the significant TRMT1-proximal proteins reveals enrichment in RNA processing and ribonucleoprotein-associated factors, in addition to hits connected to tRNA modification, tRNA biogenesis, and redox-associated biology. These data provide a proteome-scale view of TRMT1-associated cellular proteins and environments, and lay the groundwork for future validation of functional TRMT1 interaction networks.
    Significance: Fusing APEX2 enzyme to both N-terminal and C-terminal of the bait enhanced the sensitivity for identification of protein interactions.Combining APEX2-based endogenous labeling with DIA mass spectrometry increases reproducibility and depth of proximity proteome.The study provides a rich source of potential interacting or proximally close proteins to TRMT1, which warrants further validation studies.
    DOI:  https://doi.org/10.64898/2026.05.18.725941
  11. Biochimie. 2026 Jun 01. pii: S0300-9084(26)00134-3. [Epub ahead of print]247 77-84
    Functional assignments of the ubiquitination sites K62 and K230 of the human ribosomal protein uS3 (RPS3).
    Konstantin Bulygin, Anastasia Ochkasova, Andrey Krasnikov, Dmitri Graifer, Alexey A Malygin.
      Ribosomal protein uS3/RPS3 in eukaryotes is an essential component of the 40S ribosomal subunit, where it interacts with mRNA and initiation factors. It also has various extra-ribosomal functions. Proteomic studies have identified several ubiquitination sites in human uS3 that could potentially serve either as degradation signals to limit the protein level or as regulatory signals to target uS3 into cellular pathways. Currently, only uS3 ubiquitination at K214 is well understood. Here, we obtain information on functional assignment of uS3 ubiquitination at K62 and K230, using HEK293T cells producing FLAG-tagged uS3 or its forms with replacements K62R or K230R incapable of ubiquitination. Both mutations lead to a large increase of the total uS3 level in the cell indicating the involvement of the respective sites in a degradatory ubiquitination. A comparison of the level of reporter mRNAs in the total cell lysate and in the polysomal fractions revealed that both K62 and K230 are involved in the regulation of the cellular level of ribosome-free uS3 and their replacement with arginine reduces translation efficiency. Furthermore, free uS3 increases the relative levels of translated mRNA of NF-κB-dependent genes such as IL8, IL23A, and CD40, supporting its involvement in the NF-κB pathway.
    Keywords:  Factor NF-κB; HEK293T; Ribosomal protein uS3; Translation efficiency; Ubiquitination
    DOI:  https://doi.org/10.1016/j.biochi.2026.06.002
  12. Nat Commun. 2026 Jun 02. pii: 4886. [Epub ahead of print]17(1):
    Stress-induced ribosome degradation in Bacillus subtilis is mediated by the RNase Y-specificity complex.
    Fabián A Cornejo, Kristina Driller, Rina Ahmed-Begrich, Katja Schmidt, Michael Jahn, Vivekanandan Shanmuganathan, Karin Hahnke, Florian Kondrot, Thomas F Wulff, Sebastian Rämisch, Kathirvel Alagesan, Emmanuelle Charpentier, Kürşad Turgay.
      Limiting ribosome synthesis and activity is crucial for adaptation to stresses, such as heat or nutrient starvation. In Bacillus subtilis, this can be achieved through the coordinated action of the alarmones (p)ppGpp and the transcription factor Spx. Here, we performed a genetic screen to identify novel factors that contribute to the heat shock response in B. subtilis. We identified the Y-complex, which confers specificity to the endonuclease RNase Y, as a critical player under stress conditions, such as heat or transition into the stationary phase. This protein complex is required for the targeting and processing of diverse RNAs, notably the maturation of mRNAs encoding proteins involved in translation and metabolism. We further demonstrate that the Y-complex and RNase Y initiate the degradation of rRNAs of mature ribosomes, lowering their abundance. We propose that the Y-complex is a regulatory hub that modulates gene expression, adjusts protein synthesis and resource allocation.
    DOI:  https://doi.org/10.1038/s41467-026-73310-x
  13. Essays Biochem. 2026 Jun 03. pii: EBC20250018. [Epub ahead of print]
    Translation as a regulatory hub for secondary metabolism in Streptomyces spp.
    Amelia Brave, Paul D Straight.
      Streptomycetes are known for their production of diverse secondary metabolites, many of which have medicinal applications. The enzymes facilitating the production of these metabolites are encoded in biosynthetic gene clusters (BGCs) with regulatory and transport proteins. Regulation of secondary metabolite biosynthesis is tightly controlled in laboratory conditions, and many natural products have low yields or are not expressed in laboratory cultures. Although transcriptional regulation has been a major focus in the past, translational control has recently emerged as a critical determinant of BGC activity. Due to the energy requirement for translation, evidence suggests a greater degree of translational regulation than transcriptional regulation. Many translation factors impact protein synthesis rates, such as regulatory RNAs, ribonucleases, transcript quality control, ribosome rescue systems, tRNA pools, and antibiotic-induced ribosome mutations. These convergent components respond to environmental cues and metabolic states to coordinate secondary metabolism with demands for growth and development of streptomycetes. A deeper understanding of translational control will not only reveal key functions that control and coordinate specialized metabolism but will also highlight new strategies for activating silent gene clusters and enhancing natural product yields. The present review explores how translation serves as a central regulatory hub for BGC activity and discusses emerging tools to manipulate protein synthesis for natural product discovery and biotechnological advancement.
    Keywords:  antibiotics; biosynthetic gene cluster; natural products; ribosomes; secondary metabolism; translation
    DOI:  https://doi.org/10.1042/EBC20250018
  14. NAR Genom Bioinform. 2026 Jun;8(2): lqag055
    Interplay of the ribosome A and CAR sites.
    Mitsu Raval, Yancheng Zhou, Miki Lynch, Daniel Krizanc, Kelly M Thayer, Michael P Weir.
      Protein translation is a highly regulated process influenced by multiple factors at the initiation, elongation, and termination stages. One notable regulatory element of the ribosome is the CAR interaction surface, a three-residue motif in the structure of the ribosome composed of C1274 and A1427 of Saccharomyces cerevisiae 18S rRNA (corresponding to C1054 and A1196 in Escherichia coli 16S rRNA) and R146 of ribosomal protein Rps3. CAR is highly conserved and positioned adjacent to the amino-acyl (A site) decoding center. It establishes hydrogen bonds with the +1 codon next in line to enter the ribosome A site, acting as an extension of the transfer RNA (tRNA) anticodon and forming base-stacking interactions with nucleotide 34 of the tRNA. However, despite CAR's enzymatically strategic positioning within the ribosome, its functional relationship with the A site remains poorly characterized. Using molecular dynamics simulations, we examined the interplay between the A site and CAR site, revealing sequence-dependent modulation of H-bonding and π-stacking interactions within and between the two sites. These findings highlight the interplay between the A site and CAR site, suggesting a structural and functional connection between these two regions of the ribosome that may contribute to messenger RNA sequence-specific tuning of translation elongation.
    DOI:  https://doi.org/10.1093/nargab/lqag055
  15. bioRxiv. 2026 May 21. pii: 2026.05.19.726294. [Epub ahead of print]
    Divergent RNA structures support accurate splicing of the SF3B1-sensitive MAP3K7 intron.
    Austin Herbert, Alexandra Randazza, Abigail Hatfield, Lela Lackey.
      Splicing is governed by interactions between the spliceosome and precursor RNA sequence and structural elements. However, the relative contributions of RNA sequence and structural elements remain unclear. Here, we systematically dissect these determinants using a high-throughput mutagenesis approach with the MAP3K7 intron reporter. The MAP3K7 gene encodes a serine/threonine kinase involved in response to environmental stress. MAP3K7 precursor RNA contains a cryptic 3' splice site that increases in use when the core spliceosomal protein SF3B1 is mutated. SF3B1 mutations are known to promote aberrant splicing and are associated with cancer, particularly the lysine 700 to glutamate mutation (K700E). We designed a pooled library of 249 MAP3K7 mutants targeting branch points, RNA-binding protein motifs, nucleotide composition and predicted structural elements. The impact of these mutants on splicing was measured in the context of normal and SF3B1 K700E expression. RNA structure was assessed in parallel using in vitro high-throughput SHAPE-MAP chemical probing. We found that branchpoint mutations drive the strongest increases in cryptic splice-site use. There is no overall correlation between cryptic splice-site use and structural similarity to the wild-type MAP3K7 RNA. However, mutants within an RNA binding protein hotspot (containing U2AF2, U2AF1, KHSRP and SRSF2 sites) are associated with cryptic splice-site use and structural similarity to wild-type MAP3K7 RNA. These structural changes are associated with increased ensemble diversity. Our results demonstrate that although there are key structured regions within an RNA, there is also extensive variability where divergent RNA structures allow for accurate splicing.
    DOI:  https://doi.org/10.64898/2026.05.19.726294
  16. bioRxiv. 2026 May 22. pii: 2026.05.20.726645. [Epub ahead of print]
    Brief Investigation: Investigating the role of phosphodiesterase Pde2 in coordinating the yeast Environmental Stress Response.
    Rachel A Kocik, Jamie Ahrens, Audrey P Gasch.
      Yeast responding to acute stress reallocate cellular resources, in part via the Environmental Stress Response (ESR) that induces stress-defense genes while repressing ribosome-biogenesis and growth genes. The purpose and regulation of coordinated induction and repression is incompletely understood, but both responses are influenced by ESR transcription factors Msn2 and Msn4 (Msn2/4). Here we used single-cell microscopy and transcriptomic analysis to investigate the role of upstream regulator Pde2 in ESR regulation and post-stress fitness. Loss of PDE2 weakened and shortened Msn2 activation following salt stress and produced muted induction of Msn2/4 targets, similar to a msn2∆msn4∆ strain. In contrast, Pde2 had at most a minor impact on ESR repressor Dot6, yet was important for repression of its targets beyond Msn2/4 influence. Consistent with our recent resource-reallocation model, pde2∆ cells had normal or faster post-stress growth rates, despite weaker activation of the ESR. We discuss implications for ESR regulation and function.
    DOI:  https://doi.org/10.64898/2026.05.20.726645
  17. Rev Cardiovasc Med. 2026 May;27(5): 47537
    The Role of Stress Granules in Cardiovascular Diseases.
    Xiaoyu Li, Zhongjian Zhang, Luxun Tang, Shuang Li.
      Recent research has highlighted the pivotal role of RNA metabolism-related stress responses in the pathophysiology of cardiovascular diseases, particularly atherosclerosis, stroke, atrial fibrillation (AF), and heart failure (HF). Stress granules (SGs) are dynamic, membraneless organelles that arise during RNA metabolism via liquid-liquid phase separation (LLPS), in which mRNA associates with RNA-binding proteins (RBPs). SGs form following translation arrest in response to various external stimuli, resulting in cytoplasmic accumulation of mRNA and RBPs, which subsequently aggregate into membraneless messenger ribonucleoprotein (mRNP) granules, including Cajal bodies, SGs, P bodies, RNA transport granules, and germinal bodies. This review focuses specifically on SGs. SG formation is typically a transient and protective cellular response to stress; however, the dysregulation or persistence of SG formation has been implicated in a range of diseases, including cardiovascular conditions, neurodegenerative disorders, cancers, immune responses, and viral infections. Thus, this review examines the physiology and pathology of SGs, detailing the associated formation, composition, regulation, and function, with a particular focus on the involvement of SGs in cardiovascular diseases (CVDs) and potential therapeutic strategies targeting SGs. Moreover, this review outlines the complete life cycle of SGs and the associated implications in CVD. SGs originate near the endoplasmic reticulum (ER) and mitigate apoptosis by curbing mitochondrial production of reactive oxygen species. SGs can also disrupt the trafficking of specific cargo from the ER to the Golgi apparatus. Furthermore, SGs can repair damaged lysosomes and eventually undergo self-clearance via the autophagy-lysosome pathway. This model provides new perspectives for researchers in cardiovascular medicine, physicians, and translational medical researchers, and may advance our understanding of SG-related pathophysiology and facilitate the identification of novel therapeutic targets for CVDs.
    Keywords:  Golgi apparatus; RNA metabolism; cardiovascular diseases; endoplasmic reticulum; lysosome; mitochondria; stress granules
    DOI:  https://doi.org/10.31083/RCM47537
  18. J Cell Mol Med. 2026 Jun;30(11): e71224
    GPSM2 Promotes Pancreatic Cancer Progression Through METTL3-Mediated m6A Modification of YAP1 mRNA.
    Jiajun Xiu, Li Qiao, Miaomiao Li, Xiaoan Hu, Zixuan Shen, Rui Yang, Hairu Zhang, Zhe Dong, Xuelei Liu, Yinghui Zhang.
      Pancreatic cancer poses a major therapeutic challenge due to its insidious onset and difficulty in early diagnosis. G-protein signalling modulator 2 (GPSM2), a member of the G-protein signalling regulator family, is highly expressed in various tumour tissues; however, its role in pancreatic cancer remains largely undefined. Yes-associated protein 1 (YAP1), a transcriptional co-activator, has been recognised as a central node in the growth-promoting signalling pathways of pancreatic cancer. Nevertheless, whether GPSM2 contributes to pancreatic cancer progression through the regulation of YAP1 has not yet been elucidated. In this study, transcriptome analysis of 183 pancreatic cancer patients from The Cancer Genome Atlas (TCGA) dataset identified GPSM2 as a survival-associated gene in pancreatic cancer. Functionally, we demonstrated that GPSM2 promotes colony formation and invasion of pancreatic cancer cells and was found to be mechanistically linked to the regulation of YAP1. Molecular investigations revealed that GPSM2 significantly upregulated YAP1 mRNA levels. Further analysis demonstrated that GPSM2 enhanced the N6-methyladenosine (m6A) modification of YAP1 mRNA in a METTL3-dependent manner. The KH3-4 domain of the m6A reader proteins IGF2BP2 and IGF2BP3 specifically recognised the m6A-modified YAP1 transcripts, thereby stabilising YAP1 mRNA and increasing YAP1 protein expression, which in turn promoted colony formation and invasion in pancreatic cancer cells. These findings provide novel insights into the molecular mechanisms underlying pancreatic cancer progression and may offer promising therapeutic targets for future intervention.
    Keywords:  GPSM2; IGF2BP2/3; METTL3; YAP1; m6A; pancreatic cancer
    DOI:  https://doi.org/10.1111/jcmm.71224
  19. bioRxiv. 2026 May 18. pii: 2026.05.18.724443. [Epub ahead of print]
    Direct RNA Sequencing reveals epitranscriptomic regulation of brain cells and Alzheimer's Disease pathology.
    Ashley Byrne, Jonathan Hoover, Jessica Lund, Ai Zhang, Xiwei Shan, Anup Dutt Sharma, Xuewen Chen, Ana Xavier-Magalhães, Lilian Phu, Meena Choi, Ahmet Kurdoglu, Christopher M Rose, Alessandro Ori, Yuxin Liang, Alicia Nugent, Claire Jeong, Zora Modrusan, William Stephenson, Daniel Le.
      Alternative mRNA splicing and post-transcriptional RNA modification are key mechanisms that regulate transcript function; however, their role in neuronal activity and neurodegenerative disease remains poorly defined. In this study, we evaluated two nanopore-based long-read sequencing (LR-seq) formats: cDNA-PCR sequencing (CPS) and direct RNA sequencing (DRS). We then applied DRS to profile both full-length isoforms and RNA modifications in major brain cell types derived from induced pluripotent stem cells (iPSCs) and post-mortem Alzheimer's disease (AD) brains. Relative to CPS, DRS achieved higher accuracy and sensitivity for transcript quantification, de novo transcript model construction, and open reading frame (ORF) annotation across neuropathological gene sets. Focusing on iPSC-derived neurons, we built a multi-omic atlas to connect transcriptional output with translational engagement and protein abundance, by integrating DRS-based mRNA abundance, N 6 -methyladenosine (m6A) status and poly(A) tail length with ribosome profiling (Ribo-seq) and mass spectrometry (MS). The combination of DRS and Ribo-seq data demonstrated synergism in predicting protein abundance. This analysis also uncovered a significant inverse relationship between m6A modification and mRNA abundance, which was dependent on the engagement of the ribosomal A-site. Lastly, we applied DRS to the epitranscriptomic analysis of AD brain samples, demonstrating that m6A profiles can be used to distinguish early-versus late-stage disease.
    DOI:  https://doi.org/10.64898/2026.05.18.724443
  20. bioRxiv. 2026 May 19. pii: 2026.05.17.725798. [Epub ahead of print]
    TRMT6/61A-mediated m 1 A methylation facilitates human pre-tRNA maturation and prevents surveillance by XRN2.
    Xisheng Liu, Nhi Yen Tran Nguyen, Abigail Grace Johnston, Ilias Skeparnias, Monima Anam, Katherine Marlow, Naira Rehman, Andrew H Kellum, Yinsheng Wang, Jinwei Zhang, Zhangli Su.
      Transfer RNAs (tRNAs) are dynamically regulated by RNA modifications. The conserved TRMT6/61A catalyzes m 1 A ( N 1-methyladenosine) deposition at position 58. While TRMT6/61A dysregulation is linked to human diseases, its downstream processing consequences and molecular surveillance mechanisms remain unclear. Here we demonstrate that TRMT6/61A installs m 1 A on precursor tRNAs prior to processing. Utilizing a dTAG rapid depletion system, we show that acute loss of TRMT6/61A swiftly reprograms the human tRNAome. Although elongator tRNA fluctuations are buffered by isodecoder redundancy, hypomethylated tRNA iMet is selectively and rapidly degraded by the exoribonuclease XRN2, reducing global protein synthesis and activating ATF4 expression. Furthermore, m 1 A 58 is a prerequisite for tRNA end processing; its absence leads to the aberrant accumulation of unprocessed pre-tRNAs and disrupted tRNA-derived fragment (tRF) populations. Mechanistically, TRMT6/61A facilitates in vitro RNase Z cleavage, likely by promoting proper pre-tRNA folding. Lastly, XRN2 inhibition rescues tRNA iMet levels and reverses growth defects, identifying the XRN2-mediated surveillance of tRNA iMet as a primary driver of the cellular pathology. Collectively, our results uncover a pivotal role for TRMT6/61A-dependent m 1 A in human tRNA maturation and define the molecular checkpoints essential for translational homeostasis.
    DOI:  https://doi.org/10.64898/2026.05.17.725798
  21. J Toxicol Sci. 2026 ;51(6): 331-338
    A novel ICP-MS strategy identifies arsenite as an inhibitor of selenocysteine-tRNASec charging.
    Hayato Takashima, Reiko Makino, Hiroki Taguchi, Yoshika Takenaka, Yasutoshi Akiyama, Yoshihisa Tomikoka, Daigo Sumi, Takashi Toyama, Yoshiro Saito.
      Arsenite (As(III)) is a widespread environmental contaminant that increases susceptibility to oxidative stress. We recently reported that As(III) suppresses the induction of glutathione peroxidases (GPx) by various selenium sources in cultured cells; however, its underlying mechanism remains unclear. GPx contains a selenocysteine (Sec) residue essential for catalytic activity, and Sec biosynthesis requires multiple steps of selenium metabolism. Selenite is directly incorporated into the Sec biosynthetic pathway via selenophosphate synthetase 2 (SEPHS2) and utilized for Sec-tRNASec formation. Because Sec-tRNASec decodes UGA codons, impaired synthesis of Sec-tRNASec leads to nonsense-mediated decay or truncated translation of selenoprotein mRNAs. Here, we developed an inductively coupled plasma (ICP)-MS based method to evaluate Sec-tRNASec and found that As(III) inhibits Sec charging of tRNA. As(III) markedly suppressed GPx protein induction with minimal effects on mRNA abundance. As(III) did not affect total tRNASec levels; however, As(III) significantly decreased RNA-bound selenium released by deacylation, indicating reduced Sec-tRNASec formation. These results suggest that As(III) impairs selenoprotein translation by inhibiting Sec charging of tRNA.
    Keywords:  Arsenite; Glutathione peroxidase; ICP-MS; Sec-tRNASec
    DOI:  https://doi.org/10.2131/jts.51.331
  22. Biochim Biophys Acta Biomembr. 2026 Jun 03. pii: S0005-2736(26)00049-0. [Epub ahead of print] 184546
    Consequences of defective mitochondrial protein import: From targeting signals to pathology.
    Maya Cielo Cornejo, Sandy Che-Eun S Lee, Shaya Smith, Carla M Koehler.
      Cellular organelles are uniquely specialized membrane-bound structures that enable cells to organize and coordinate biochemical processes. Specifically, mitochondria are essential organelles for cellular metabolism, coordinating energy production, and connecting signaling networks for cellular homeostasis. 99% of mitochondrial proteins are encoded by nuclear genes that require precise and efficient translation and import into mitochondria for biological processes. This process is mediated by coordinated pathways involving the mitochondrial specific translocation complexes, chaperones, and specialized targeting routes. Tight regulation of these import mechanisms allows for proper protein localization, folding, and assembly. Disruptions in the mitochondrial protein import pathway compromise organelle homeostasis and activate proteostatic stress and quality control pathways. Such defects have been observed in a wide range of pathophysiological conditions, including cardiovascular disease, neurodegeneration, and cancer. The import defects destabilizing mitochondrial proteins can impair oxidative phosphorylation and metabolic signaling. In sum, defects to mitochondrial function can highlight a central role of mitochondrial protein import beyond maintaining cellular function and how defects at distinct stages of import contribute to disease, underscoring opportunities for therapeutic intervention targeting mitochondrial proteostasis.
    Keywords:  Mitochondria; Mitochondrial disorders; Mitochondrial protein import; Mitochondrial protein processing; Mitochondrial targeting sequence; Proteostasis; TIM23 complex; TOM complex
    DOI:  https://doi.org/10.1016/j.bbamem.2026.184546
  23. bioRxiv. 2026 May 19. pii: 2026.05.17.725791. [Epub ahead of print]
    Nascent protein retention at polysomes reduces kinetic barriers to self-assembly.
    Shriram Venkatesan, Alex Von Schulze, Jeffrey J Lange, Jacob Jensen, Lexie E Berkowicz, Dai Tsuchiya, Ning Zhang, Jennifer Gardner, Scott McCroskey, Ying Zhang, Selene Swanson, Yan Hao, Malcolm Cook, Tong Shu, Liam J Holt, Laurence Florens, Jay R Unruh, Randal Halfmann.
      Living proteomes are necessarily far from equilibrium. It is paradoxical, then, that reducing the translation of new proteins -- which should promote equilibration -- instead prolongs life. We investigated the impact of translational flux to nucleation barriers that preserve the solubility of proteins destined to form amyloids or other assemblies. By manipulating translation initiation rates directly or indirectly, across yeast and human cells, and across a variety of supersaturable proteins, we find that accelerating translation initiation broadly accelerates nucleation irrespective of their global concentrations. We showed that this effect was confined to polysomes and was enhanced by N-terminal placement or other features that retained the nascent aggregating domain at polysomes. Finally, we show that intrinsically disordered regions with high tendencies to self-associate are specifically positioned to do so co-translationally, providing evidence that cotranslational nucleation has shaped proteome evolution.
    DOI:  https://doi.org/10.64898/2026.05.17.725791
  24. Nucleic Acids Res. 2026 May 20. pii: gkag510. [Epub ahead of print]54(10):
    Structural studies of nedicistrovirus IRES-driven, initiation factor-independent translation shed light on key steps of eukaryotic translation elongation.
    Swastik De, Clara G Altomare, Irina S Abaeva, Prikshat Dadhwal, Priyanka Garg, Francisco Acosta-Reyes, Zuben P Brown, Tatyana V Pestova, Christopher U T Hellen, Joachim Frank.
      We utilized the nedicistrovirus (NediV) intergenic region (IGR) internal ribosomal entry site (IRES)-mediated, initiation factor-independent translation initiation system and determined high-resolution structures of 80S ribosome complexes with the NediV IRES in various functional states, including binary complexes, aminoacyl-transfer RNA (tRNA)-bound complexes, and complexes with elongation factor eEF2. In binary complexes, the NediV IRES primarily occupies the ribosomal P site, exhibiting conformational flexibility and engaging the ribosome at multiple interaction sites. Upon translocation, the IRES undergoes structural rearrangements, including destabilization of its PKI domain, facilitating the transition to canonical elongation. Crucially, we captured an eEF2-bound complex, along with an eEF1A-bound failed decoding complex featuring a mismatched tRNA, the latter representing the first instance of a canonical elongation complex visualized in the presence of a natural, hydrolysable nucleotide and without the addition of any trapping agents. These findings provide a comprehensive structural overview of IGR IRES-mediated translation initiation and its transition to elongation, revealing key mechanistic details of viral translation and proofreading.
    DOI:  https://doi.org/10.1093/nar/gkag510
  25. J Inflamm Res. 2026 ;19 606604
    Endoplasmic Reticulum Stress as a Stage-Dependent Regulatory Hub in Rheumatoid Arthritis.
    Na Hu, Yaguang Song, Ting Yu, Hongbo Li, Xin Wang, Qingguo Lv.
      Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Beyond its canonical role in maintaining proteostasis, growing evidence indicates that endoplasmic reticulum (ER) stress acts as a dynamic regulatory hub integrating inflammatory signaling, metabolic reprogramming, and cell fate control within the RA synovium. Activation of the unfolded protein response (UPR) sensors-IRE1α, PERK, and ATF6-initially promotes adaptive compensation aimed at restoring ER homeostasis. However, sustained or maladaptive signaling drives inflammatory amplification, apoptosis resistance in fibroblast-like synoviocytes (FLS), immune dysregulation, and enhanced osteoclastogenesis. Recent studies further reveal stage-dependent and cell type-specific patterns of ER stress activation, underscoring its context-dependent pathogenic functions during disease initiation and progression. Accordingly, therapeutic strategies are shifting from broad suppression of ER stress toward precision modulation of discrete UPR modules, including alleviation of excessive proteostatic burden and selective induction of pro-apoptotic signaling in pathogenic synoviocytes. By integrating mechanistic insights with translational perspectives, this review highlights ER stress as a context-dependent signaling network and a potential precision therapeutic target in RA.
    Keywords:  endoplasmic reticulum stress; fibroblast-like synoviocytes; rheumatoid arthritis; unfolded protein response
    DOI:  https://doi.org/10.2147/JIR.S606604
  26. FEBS Open Bio. 2026 Jun 04.
    Hyperosmotic stress-induced redistribution of pre-mRNA cleavage factor I subunits is associated with shifts in alternative polyadenylation.
    Hitomi Soumiya, Masatake Osawa, Hidefumi Fukumitsu.
      Alternative polyadenylation (APA) is an important mechanism of cellular stress response mediated in part by the cleavage factor Im (CFIm) complex. However, the spatiotemporal dynamics and regulatory activity of the mammalian CFIm complex during stress remain poorly understood. In this study, we determined the effect of moderate hyperosmotic stress on CFIm localization and APA profiles in HEK293 cells. Using a dual-normalization strategy that included 18S rRNA- and a CDS-based ratiometric qPCR, we identified a significant shift toward proximal polyadenylation sites (PAS) in the established CFIm targets, NUDT21 (encoding CFIm25) and DICER1. Notably, these APA dynamics displayed distinct kinetic profiles influenced by the metabolic environment: While the NUDT21 L-3'UTR/CDS ratio recovered to baseline by Day 4, DICER1 exhibited a serum-dependent response, showing a progressive decline under low-serum conditions but recovering under high-serum conditions. Crucially, these alterations were absent in non-target multi-PAS genes such as GOLGA2 and preceded any substantial reduction in total mRNA abundance, suggesting these effects represent a targeted regulatory event rather than a nonspecific byproduct of transcriptional decline. Mechanistically, hyperosmotic stress triggers a transient, coordinated redistribution of CFIm25 and CFIm68 from the nucleus to the cytoplasm, while total cellular protein concentrations remain stable. We propose that this spatial shift creates a 'stoichiometric bottleneck' within the nuclear CFIm pool, effectively limiting the processing of distal PAS. This 'stoichiometric stress response' offers a robust mechanistic framework linking subnuclear protein reorganization to the rapid reprogramming of the 3'UTR landscape, providing new insights into how cells modulate gene expression potential during osmotic adaptation.
    Keywords:  CFIm25 (NUDT21); alternative polyadenylation; hyperosmotic stress; mammalian pre‐mRNA cleavage factor I (CFIm); stoichiometric stress response
    DOI:  https://doi.org/10.1002/2211-5463.70278
  27. Nucleic Acids Res. 2026 May 20. pii: gkag538. [Epub ahead of print]54(10):
    Muscleblind-like proteins dimerize by forming disulfide bonds to regulate alternative splicing and pathogenic RNA foci formation.
    Luke A Knudson, Adam Kosti, Ryan P Hildebrandt, Ethan Jennings, Eric X Zhou, Kathryn R Moss, Liang Shi, GiaLinh N Nguyen, Aleksandra Janusz-Kaminska, Eric T Wang, Gary J Bassell.
      Muscleblind-like (MBNL) RNA-binding proteins (RBPs) possess modular domains that mediate regulation of alternative splicing and RNA localization. In Myotonic Dystrophy Type 1, a CTG repeat expansion disorder, MBNL is sequestered into intranuclear RNA foci, impairing its function. Previous studies found that MBNL self-associates through its exon 7, but the nature of this interaction is not well understood. We identified a cysteine in MBNL1 exon 7 that enables dimerization through the formation of an intermolecular disulfide bond. We likewise demonstrate that MBNL2 dimerizes by forming disulfide bonds between multiple cysteines in its carboxy-terminus. Nucleocytoplasmic fractionation revealed a greater proportion of MBNL1 dimer in the nucleus, suggesting a nuclear function for the MBNL1 dimer. We investigated a connection between MBNL1 dimerization and MBNL1-mediated regulation of alternative splicing. To accomplish this, we mutated the MBNL1 cysteine in question to alanine (C325A) and performed RNAseq. We uncovered novel splicing events sensitive to MBNL1 dimerization. We also found that MBNL1 C325A, when co-expressed with expanded CTG repeats, produces smaller, more numerous foci, suggesting a role for the MBNL1 dimer in maintaining foci integrity. These results provide insight into biological and pathological mechanisms of MBNL1 dimerization and suggest that other RBPs might similarly dimerize to regulate function.
    DOI:  https://doi.org/10.1093/nar/gkag538
  28. Eur J Pharmacol. 2026 Jun 04. pii: S0014-2999(26)00515-7. [Epub ahead of print] 179033
    Ribosome impairment, tau alternative splicing, and stress granules: a convergent axis of neuronal vulnerability driving Alzheimer's disease.
    Mirco Masi, Chiara Oliviero, Stefano Govoni, Benjamin Wolozin, Marco Racchi, Erica Buoso.
      Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by the pathological aggregation and deposition of amyloid-β (Aβ) plaques and tau neurofibrillary tangles. However, accumulating evidence points at the disruption of RNA metabolism and translational control as central players in the disease progression. Emerging studies suggest that pathogenic mechanisms previously considered separately - namely ribosome biogenesis impairment, dysregulation of tau alternative splicing, and persistent stress granule (SG) formation - could be components of an integrated axis of neuronal vulnerability contributing to early AD pathogenesis. In AD, ribosomal loss and rDNA transcriptional silencing correlate with tau hyperphosphorylation and tau-ribosome interaction, while SG-mediated sequestration of splicing factors may exacerbate 3R/4R tau imbalance, promoting aggregation-prone isoforms. These processes appear to mutually reinforce through neuroinflammation and chronic translational stress, driving progressive proteostatic failure and cognitive decline. Converging evidence across systems (histopathological, in vivo and in vitro models) strongly suggest the existence of a ribosome-tau splicing-SG axis that operates at a pre-aggregative phase of the disease. In this context, this early disruption of translational homeostasis may trigger neuronal vulnerability decades before Aβ and tau aggregation as well as symptomatic disease. In this review, we synthesize current evidence supporting a stepwise, feed-forward model that links ribosome dysfunction, splicing alterations, and chronic SG persistence in AD. Our hypothesized integrated framework highlights potential pharmacological routes each capable of targeting distinct pathogenic nodes of the axis to restore translational homeostasis and reduce neuronal vulnerability, thus outlining potential upstream intervention strategies beyond the traditional Aβ- and tau-centric therapeutic approaches.
    Keywords:  RNA-binding protein (RBPs); liquid-liquid phase separation (LLPS); nucleolar stress response; proteostasis; rDNA silencing; tau 3R/4R ratio
    DOI:  https://doi.org/10.1016/j.ejphar.2026.179033
  29. bioRxiv. 2026 May 22. pii: 2026.05.21.726978. [Epub ahead of print]
    SnoRNA Expression and RNA 2'-O-Methylation in Drosophila melanogaster S2 Cells.
    Xuan Ye, Yaling Liu, Sara Olson, Lijun Zhan, Gordon G Carmichael, Brenton R Graveley.
      Small nucleolar RNAs (snoRNAs) are a class of non-coding RNAs that play critical roles in guiding 2'-O-methylation (Nm) and pseudouridylation modifications of RNAs. In Drosophila melanogaster , snoRNAs undergo dynamic changes in expression during development. In this study, we identified 239 snoRNAs that are robustly expressed in Drosophila S2 cells, representing 87% of all annotated Drosophila snoRNAs. Given that box C/D snoRNAs guide site-specific 2'-O-methylation (Nm) of RNA, we next characterized the Nm landscape of S2 cells using RibOxi-seq2, a high-throughput approach capable of detecting Nm modifications with single-nucleotide resolution. RibOxi-seq2 revealed 17 Nm sites in 18S rRNA with a 94% concordance to previously reported RiboMeth-Seq data. In 28S rRNA, 30 Nm sites were identified, corresponding to an 71.4% overlap with established references. Additionally, we detected both a known Nm site (Gm74) and a novel site (Um66) in 5.8S rRNA, further validating the sensitivity and specificity of the approach. RibOxi-seq2 further identified Nm sites in small nuclear RNAs (snRNAs), expanding the annotation of modified non-coding RNAs. Additionally, the method revealed Nm modifications within internal regions of mRNAs. In total, we detected Nm modifications in 2,057 unique mRNAs, underscoring the widespread presence of this epitranscriptomic modification in coding transcripts. Strikingly, although we could not identify any snoRNAs predicted to guide the mRNA 2'-O-methylation modifications by canonical mechanisms, we identified strong consensus sequences surrounding many of these mRNA sites. Together, our findings not only expand the known landscape of Nm-modified RNAs but also highlight the robustness of RibOxi-seq2 for transcriptome-wide RNA modification profiling. Collectively, this study presents a comprehensive atlas of snoRNA expression and 2'-O-methylation sites in Drosophila S2 cells, offering valuable insights into the epitranscriptomic landscape orchestrated by snoRNAs.
    DOI:  https://doi.org/10.64898/2026.05.21.726978
  30. bioRxiv. 2026 May 20. pii: 2026.05.19.726202. [Epub ahead of print]
    An RNA Language Model trained on sequence alone reveals the structural logic of Internal Ribosome Entry Sites.
    Adam Sychla, Pierre Bongrand, Grant Yang, Jacob Rulison, R Alexander Wesselhoeft, Namita Bisaria, Silvi Rouskin.
      Viral RNA genomes are among the most information-dense codes in biology. In picornaviruses, translation depends entirely on Internal Ribosome Entry Sites (IRESes), yet their structures remain largely unresolved. Previous studies either screened short IRES fragments in high throughput or characterized full-length elements individually. Here, we profile 96 full-length IRESes across six cell types, revealing that recently described Type V IRESes double the activity of EMCV, the standard in bioengineering, and that most IRESes exhibit significant tissue tropism. We introduce Albatross, an RNA language model fine-tuned on 50,000 IRES sequences. Trained on sequence alone, Albatross predicts IRES structures with precision comparable to chemical probing, outperforming covariation anal-ysis. We generate structure maps for ∼75,000 full-length IRESes and show that structural discovery scales with model size.
    DOI:  https://doi.org/10.64898/2026.05.19.726202
  31. bioRxiv. 2026 May 28. pii: 2026.05.26.728043. [Epub ahead of print]
    rDNA breaks activate dsRNA pattern recognition through sense-antisense transcription.
    Jie Chen, Sangin Kim, Sixing Chen, Zongchao Mo, Yiyang Jiang, Kathy Fange Liu, Qin Li, Roger A Greenberg.
      Myriad DNA damaging chemo- and radio- therapies interfere with ribosomal RNA (rRNA) transcription and processing, yet the biological consequences of these phenomena remain unclear. Here we show that aberrant transcripts emanating from rDNA breaks engage double-stranded RNA pattern recognition receptors, melanoma differentiation-associated protein 5 (MDA5) and retinoic acid-inducible gene I (RIG-I) to activate immune signaling. rDNA damage abolishes full-length rRNA synthesis while generating truncated sense-antisense rRNA transcripts, whose accumulation is restrained by ATM and ATR kinase activities. Purification of the endogenous MDA5-filament coupled with sequencing identified complementary sense and antisense rRNA transcripts that terminate and initiate near the break site, respectively. This implicates aberrant rRNA species as a major source of damage induced endogenous ligands for dsRNA pattern recognition and establishes a mechanism by which nucleolar stress is coupled to immune signaling.
    DOI:  https://doi.org/10.64898/2026.05.26.728043
  32. Front Cell Dev Biol. 2026 ;14 1850701
    FTO in cardiovascular diseases: mechanisms, context dependence, and translational opportunities.
    Yifan Kong, Di Zhang.
      Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. Their regulation involves not only classical genetic mechanisms but also dynamic epitranscriptomic control. The fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m6A) RNA demethylase, has been implicated in cardiovascular disease. Evidence shows that the role of FTO in CVDs is strongly context dependent, with both protective and harmful effects reported in different settings. This review summarizes the genetic, molecular, and epitranscriptomic features of FTO and presents a framework in which FTO acts through three connected axes: metabolic remodeling, immuno-inflammatory signaling, and electrophysiological and structural remodeling. By regulating key transcripts through RNA methylation-related post-transcriptional control, FTO may modulate cellular responses to hypoxia, inflammation, and metabolic stress. It also reviews the context-specific roles of FTO in atherosclerosis, hypertension, myocardial infarction, ischemia-reperfusion injury, myocardial fibrosis, heart failure, arrhythmia and myocarditis. These different effects seem to depend on cell type, target selection, and disease stage, which suggests that FTO acts as a context-sensitive epitranscriptomic switch rather than a simple one-way effector. FTO represents a promising but complex therapeutic target. Pharmacological inhibition of FTO has shown benefit in some disease settings, but other studies suggest that selective activation or context-dependent modulation may also be needed. However, the precise biochemical functions of FTO and the relative contributions of RNA modifications remain incompletely understood. Key barriers include limited causal evidence, poor cell-specific resolution, and incomplete integration with other epigenetic layers.
    Keywords:  FTO; RNA methylation; cardiovascular diseases; context-dependent regulation; epitranscriptomics
    DOI:  https://doi.org/10.3389/fcell.2026.1850701
  33. Vet Immunol Immunopathol. 2026 Jun 01. pii: S0165-2427(26)00084-X. [Epub ahead of print]299 111144
    HPAIV-induced heat shock protein expression in chickens and its potential NF-κB-mediated transcriptional regulation.
    Jae Rung So, Anh Duc Truong, Thu Uyen Nguyen, Andrew Wange Bugenyi, Ha Thi Thanh Tran, Hoang Vu Dang, Ki-Duk Song.
      During infection with highly pathogenic Avian Influenza virus (HPAIV), heat shock proteins (HSPs) play roles in host immune responses by interacting with various regulators of cell signaling pathways and in mediating cellular homeostasis. However, the tissue-specific regulation of these chaperones, particularly their potential association with the NF-κB pathway, remains poorly defined in avian species. Chickens were infected with HPAIV (A/chicken/Vietnam/NA01/2019 (H5N1), and the expression patterns of a comprehensive range of HSPs (small HSPs to canonical classes) were analyzed in lung and spleen at 1 and 3 days post-infection (dpi). As a result, HPAIV infection induced significant temporal up-regulation of mRNA of small sHSPs (sHSPs; HSPB7, HSPB9), HSPE1, and a collagen-specific molecular chaperone, SERPINH1, in both tissues. To investigate transcriptional regulation, DF-1 cells were stimulated with Poly(I: C) in the presence or absence of NF-κB inhibitors. Notably, NF-κB inhibition was associated with an up-regulation of HSPB9 and a depression of SERPINH1 in PIC-treated DF-1. These results suggest that specific HSPs may be influenced by pro-inflammatory signaling during viral infection, with NF-κB signalling potentially contributing to their negative regulation during viral stress response. Collectively, these findings provide preliminary insights into the complex molecular dynamics of HPAIV pathogenesis and highlight the importance of host-mediated signaling pathways in modulating the host cellular stress response in poultry.
    Keywords:  HPAIV; HSFs; Heat Shock Proteins (HSPs); NF-κB signaling pathway
    DOI:  https://doi.org/10.1016/j.vetimm.2026.111144
  34. Nat Commun. 2026 Jun 03.
    Elp3 uses a conserved molecular tunnel to transport acetate between distant active sites and catalyze tRNA wobble base modification.
    Evan P Geissler, Youmna Moawad, Paige N Roehling, Cassidy Driscoll, Katherine Martin, Papa Nii Asare-Okai, Jeffrey S Mugridge.
      The radical SAM enzyme Elp3 and eukaryotic Elongator complex catalyze formation of a key intermediate transfer RNA (tRNA) modification, 5-carboxymethyluridine (cm5U), in the anticodons of tRNAs across all domains of life. cm5U-derived modifications are important for fine tuning codon-anticodon interactions and efficient protein translation, and defects in this modification are linked to development of neurodegenerative disease in humans. Here we reconstitute tRNA modification activity with a model Elp3 enzyme and combine structural analyses, enzymology, and isotope incorporation experiments to show Elp3 harbors a conserved molecular tunnel that shuttles free acetate molecules from the acetyl-CoA binding domain to the radical SAM active site over 20 Å away, where acetate undergoes radical-mediated reaction and addition to tRNA U34. Our model explains how Elp3 bridges a large distance between active sites to catalyze tRNA carboxymethylation and illustrates a unique mechanism for intermediate transport in radical SAM enzymes.
    DOI:  https://doi.org/10.1038/s41467-026-73699-5
  35. bioRxiv. 2026 May 18. pii: 2026.05.17.725762. [Epub ahead of print]
    Cell-type-resolved RNP topologies reveal dynamic structural mechanisms of splicing and therapeutic targets.
    Jianhui Bai, Kongpan Li, Wei Zhang, Minjie Zhang, Grant Shoffner, Willem A Velema, Jianfu Chen, Feng Guo, Zhipeng Lu.
      Resolving RNA conformations in native ribonucleoprotein (RNP) complexes remains a fundamental challenge. Here, we introduce spatial hydroxyl acylation reversible crosslinking with immunoprecipitation (SHARCLIP) to simultaneously capture RNA-RNA, RNA-protein and protein-protein contacts in cells. SHARCLIP profiling of HNRNPC-associated RNA conformations established a global phased map of ribonucleosomes, resolving a decades-old debate on heterogenous nuclear (hn)RNP assembly. We built a dynamic structural atlas across seven cell lineages for >10,000 RNAs, generating ~200 million contacts, and identifying millions of dynamic loops, steric blockers and conformational switches that control splicing outcome. Deciphering the structural logic of mutually exclusive exons (MXEs) enabled rational design of structure-breaking and stabilizing antisense oligonucleotides (ASOs). We demonstrate effective isoform swapping in 12 genes linked to genetic disorders. SHARCLIP provides a comprehensive roadmap for cellular RNA structural biology and structure-guided RNA therapeutics.
    DOI:  https://doi.org/10.64898/2026.05.17.725762
  36. Res Sq. 2026 May 22. pii: rs.3.rs-9655893. [Epub ahead of print]
    Metabolically Induced Intestinal Inflammation: The Role of ER Stress and Autophagy in a Porcine Model of Diabetes.
    Ugljesa Malicevic, Ranko Skrbic, Devendra K Agrawal.
      The mechanisms linking chronic hyperglycemia to intestinal inflammation and epithelial dysfunction remain incompletely understood, highlighting an important gap in our understanding of diabetes-associated gastrointestinal pathology. In this study, we investigated the effects of sustained hyperglycemia on intestinal inflammation, endoplasmic reticulum (ER) stress, and autophagy in a translational porcine model of diabetes. Diabetes was induced in Yucatan mini pigs using a high-fat, high-carbohydrate/fructose diet (HFHFD) followed by streptozotocin administration. Intestinal tissues from the terminal ileum and sigmoid colon were analyzed using histological evaluation, quantitative real-time PCR, and immunohistochemistry. Histological analysis revealed structural alterations in diabetic animals, including villous degeneration, crypt depletion, goblet-cell loss, and increased inflammatory-cell infiltration. Gene expression analysis revealed significant upregulation of inflammatory mediators (NF-κB, TNF-α, IL-6, IL-1β), inflammasome components (NLRP3), and macrophage markers (CD68, CD86, CD163). In parallel, ER stress-related genes (ORMDL3, ATF6) and autophagy-associated genes (NOD2, ULK1, ATG4a) were significantly elevated in diabetic pigs. At the protein level, increased expression of ER stress markers was confirmed in both intestinal regions, while autophagy-related proteins showed less consistent changes and did not fully reflect the observed transcriptional patterns, suggesting a potential disconnect between transcriptional activation and functional autophagic response under diabetic conditions. Chronic hyperglycemia is associated with intestinal inflammation and disruption of cellular stress pathways, including ER stress and autophagy, in a porcine model. These findings provide mechanistic insight into how chronic hyperglycemia contributes to intestinal dysfunction through coordinated alterations in inflammatory signaling, ER stress, and autophagy pathways, identifying these processes as potential targets for therapeutic intervention in diabetes-associated gastrointestinal disease.
    DOI:  https://doi.org/10.21203/rs.3.rs-9655893/v1
  37. Plant Cell Environ. 2026 Jun 04.
    Molecular Chaperone Networks in Plants: Maintaining Proteostasis and Enhancing Stress Resilience for Crop Improvement.
    Mingfang Yang, Anqin Gao, Tsz-Yan Chan, Hafiz Mamoon Rehman, Sehar Nawaz, Sehrish Bashir, Noman Mahmood, Muhammad Wajid Ullah, Chunlin Long, Hon-Ming Lam, Muhammad Arif.
      Molecular chaperones play a central role in the plant proteostasis machinery by aiding the folding of nascent proteins, preventing aggregation, and repairing or degrading damaged proteins. These functions are especially essential during abiotic and biotic stress, which can destabilise cellular proteins and disrupt metabolic homoeostasis. This review summarises the current progress regarding the major heat shock protein (Hsp) families, Hsp100, Hsp90, Hsp70, Hsp60, and small heat shock proteins (sHSPs) and their key co-chaperones, DnaJ/Hsp40 and nucleotide exchange factors (NEFs), in relation to their structural characteristics, subcellular targeting, and heat shock factor (HSF)-mediated regulatory pathways. We emphasise certain examples, such as the role of Hsp101 in acquired thermotolerance or the use of sHsps as ATP-independent aggregation preventers. Transcriptional, proteomic, and interactomic analyses have shown changes in chaperone abundance and activity during stress, but there is a major gap in the understanding of how chaperone networks respond to combined, field-relevant stress. Recent biotechnological uses, such as CRISPR/CAS9-based knockout of OsHSBP1 in rice and transgenic overexpression of TaHSP17.4 in wheat, show concrete support of stress tolerance and stability in yield. Combining biochemical processes with the emerging biotechnological understanding, this review highlights how the manipulation of chaperone networks can be targeted to enhance the pace at which crops, capable of withstanding climate change, can be developed, and assist in supporting the sustainable productivity of agriculture.
    Keywords:  HSF signalling; abiotic stress; chaperone networks; crop resilience; heat shock protein; molecular chaperone; multi‐omics; plant stress tolerance; protein quality control; proteostasis
    DOI:  https://doi.org/10.1111/pce.70629
  38. Brain Res Bull. 2026 May 31. pii: S0361-9230(26)00260-1. [Epub ahead of print] 111974
    Stress Granules and Tau Pathology in Alzheimer's Disease: A Scoping Review of Bidirectional Interactions, Liquid-Liquid Phase Separation, and Proteostatic Consequences.
    Bita Ashrafi Kashtiban, Maryam Rezazadeh, Jalal Gharesouran, Behboud Jafari, Soudeh Ghafouri-Fard.
       BACKGROUND: Alzheimer's disease (AD) is characterized by progressive neurodegeneration driven by amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Stress granules (SGs), dynamic ribonucleoprotein condensates formed under cellular stress have been implicated in several neurodegenerative disorders, but their role in AD pathogenesis remains incompletely understood.
    METHODS: Following PRISMA-ScR guidelines, we systematically searched PubMed, Embase, Scopus, Web of Science, and Cochrane Library (through February 2026) for peer-reviewed studies investigating SGs in AD models or human tissue. Two reviewers independently screened records, extracted data, and performed narrative synthesis.
    RESULTS: Thirty-five studies met inclusion criteria. TIA1 (51.4%) and G3BP1 (42.9%) were the most frequently used SG markers. Multi-model designs incorporating human tissue validation predominated (40.0%). Evidence suggests a bidirectional pathogenic interplay: tau pathology promotes SG assembly and persistence, while SG proteins, particularly TIA1 and USP10 can drive tau oligomerization and toxicity via liquid-liquid phase separation in experimental models. Additional SG network components, including HDAC6 and TRIM21, have been independently implicated in AD pathology, though they remain less explored in direct SG-tau interaction studies. Conversely, G3BP2 exerts protective effects by directly binding tau and inhibiting aggregation. SG dysregulation is associated with disrupted RNA metabolism, sequesteration of AD-associated transcripts, and impaired autophagy. Therapeutic strategies targeting SG modulation, including autophagy enhancers (mTOR inhibitors, myricetin), show promise in reducing tau pathology and SG burden in preclinical systems.
    CONCLUSION: The reviewed evidence suggests that SGs are associated with AD pathogenic processes through bidirectional interactions with tau pathology, RNA dysregulation, and proteostatic collapse. These findings, derived largely from preclinical models, support further investigation into SG modulation as a potential therapeutic strategy for AD, while definitive causal roles in human disease remain to be established.
    Keywords:  Alzheimer's disease; SGs; liquid-liquid phase separation; neurodegeneration; tau protein; therapeutic target
    DOI:  https://doi.org/10.1016/j.brainresbull.2026.111974
  39. bioRxiv. 2026 May 26. pii: 2026.05.22.726816. [Epub ahead of print]
    Oncofetal RNA-binding proteins of IGF2BP family suppress IRF-3 and NF-kB dependent transcription downstream of cytosolic RNA sensors.
    Garrett Knox, Ruba Agili-Shaban, Alexis Morrissey, Karamveer Karamveer, Ahsan Polash, Maria Wohlbowne, Stefanija Kinzy, Cheryl Keller, Todd Schell, Jeremy Hengst, George-Lucian Moldovan, Junjia Zhu, Arati Sharma, Hong Zheng, Edward Harhaj, Markus Hafner, Zhenqiu Liu, Yasin Uzun, Shaun Mahony, Irina Elcheva.
      Activation of innate inflammatory signaling and tumor-specific antigen presentation in cancer cells provides a foundation for anti-cancer immunotherapies. Here, we show that Insulin-like Growth Factor 2 mRNA-Binding Proteins (IGF2BP1, IGF2BP2, and IGF2BP3), which are upregulated across various human malignancies, including acute myeloid leukemia (AML), suppress the activity of RNA-sensing pattern recognition receptors and downstream ISRE- and NF-κB-driven transcription. IGF2BPs exert a strong inhibitory effect on RIG-I signaling. This suppression is most pronounced when all three paralogs are co-expressed, particularly in embryonic-like hematoendothelial and leukemia stem cells. IGF2BPs suppress innate immune signaling via direct binding with TNFAIP3 mRNA and support of its RNA and protein expression. Genetic and pharmacological inhibition of IGF2BPs activates innate immune signaling and induces MHC class I gene expression in AML, highlighting a promising strategy for RIG-I- and TLR-based cancer immunotherapies.
    DOI:  https://doi.org/10.64898/2026.05.22.726816
  40. bioRxiv. 2026 May 22. pii: 2026.05.20.726545. [Epub ahead of print]
    FBXL21 regulates diurnal proteostasis and stress response by targeting DNAJB6 and client proteins.
    Ji Ye Lim, Jaebok Wi, Marvin Wirianto, Chorong Han, Sun Young Kim, Jane Nguyen, Sehyun Jung, Kristin Eckel-Mahan, Sung Yun Jung, Karyn A Esser, Zheng Chen, Seung-Hee Yoo.
      Circadian regulation of proteostasis, a key determinant of muscle health, remains poorly understood. Here, we identified DNAJB6, an Hsp40 (DnaJ) co-chaperone, as a substrate of the circadian E3 ligase FBXL21. FBXL21 mediated the ubiquitination-dependent proteasomal degradation of both DNAJB6 and its client proteins including Desmin; causative mutations of DNAJB6 in myopathies, however, rendered resistance to FBXL21-directed degradation. Fbxl21 KO C2C12 cells displayed aberrant accumulation of Desmin, and showed aggravated cytoplasmic accumulation of TDP-43, another DNAJB6 client protein, in heat shock response. Under timed exercise as a physiological stressor, WT mice displayed robust diurnal rhythms in the levels of stress granule markers (G3BP1 and FUS) and TDP-43 as a function of exercise timing. In contrast, the Fbxl21 hypomorph Psttm mutant mice showed elevated expression of these proteins without exercise, which was exacerbated under exercise-induced stress conditions; importantly, these abnormalities were rescued by skeletal muscle-specific FBXL21 expression. Our study elucidates a novel diurnal regulatory mechanism of skeletal muscle proteostasis via FBXL21 as a chaperone-linked E3 ligase, highlighting the FBXL21-DNAJB6 axis as a potential therapeutic target for myopathies.
    DOI:  https://doi.org/10.64898/2026.05.20.726545
  41. J Gastroenterol Hepatol. 2026 Jun 02.
    METTL3-Mediated m6A Modification of FYN: Regulating Tumor-Associated Endothelial Cells in Colorectal Cancer Progression.
    Qiang Su, Kaiyue Wang, Ruohan Liao, Hanyu Zhang, Bochu Wang.
       BACKGROUND AND OBJECTIVE: Colorectal cancer (CRC) presents complex challenges in treatment and prognosis. This study aims to elucidate the role and mechanism of FYN in colorectal cancer progression and its potential as a prognostic marker.
    METHODS: The expression of FYN in colorectal cancer and adjacent tissues was assessed using qPCR and Western blot analyses, complemented by data from The Human Protein Atlas and Kaplan-Meier Plotter databases. The regulatory effects of FYN on Slit2 expression via the mTOR pathway were explored through genetic manipulation in various colorectal cancer cell lines. Additionally, the impact of FYN expression on properties of tumor-associated endothelial cells (TAECs) was investigated through co-culture experiments. The m6A methylation modulated FYN expression was evaluated by analyzing the effect of METTL3 on FYN mRNA stability.
    RESULTS: FYN was significantly upregulated in colorectal cancer tissues, correlating positively with tumor size, stage, and metastasis. High FYN expression was associated with poor survival outcomes. Regulatory effects of FYN on Slit2 expression via the mTOR pathway were evident. Enhanced FYN expression facilitated endothelial-to-mesenchymal transition (EndMT), angiogenesis, and compromised barrier function in TAECs. METTL3 was found to stabilize FYN mRNA through m6A methylation, influencing FYN expression and downstream effects on Slit2 via the mTOR pathway.
    CONCLUSION: FYN plays a crucial role in colorectal cancer progression, influencing tumor growth, metastasis, and patient prognosis through the regulation of Slit2 expression and TAECs properties. METTL3-mediated m6A methylation of FYN mRNA is a key mechanism in maintaining FYN stability, suggesting potential therapeutic targets in colorectal cancer treatment.
    Keywords:  FYN; METTL3; colorectal cancer; endothelial cells; m6A
    DOI:  https://doi.org/10.1111/jgh.70329
  42. RNA. 2026 Jun 02. pii: rna.081054.126. [Epub ahead of print]
    Cytosolic and ER-associated ribosomes share rRNA 2'-O-methylation landscapes across human cell types.
    Ülkü Uzun, Anders H Lund.
      Ribosome heterogeneity arising from variable rRNA 2'O methylation (2'O Me) has been proposed as a potential mechanism for translational specialization, but whether such heterogeneity contributes to compartment specific translation remains unknown. Here, we systematically compare the 2'O Me landscapes of cytosolic and endoplasmic reticulum (ER)-associated ribosomes across three human cell types: HEK293 cells, H9-derived neural progenitor cells (NPCs), and neurons differentiated from these NPCs. Using detergent-based fractionation combined with RiboMeth-seq, we generate site-resolved rRNA methylation profiles for each compartment. Within each cell type, cytosolic and ER-associated ribosomes display highly similar 2'O Me patterns, with only modest compartment-specific differences observed at 18S:462 in NPCs and 28S:2043 in neurons. Across all samples, differences in 2'O Me patterns are more pronounced between cell types than between compartments. Together, these findings indicate that 2'O Me does not establish a broad ER-specific methylation signature and is unlikely to be a major determinant of ribosome localization or function at the ER.
    Keywords:  Local translation; Neuronal translation; RiboMeth-seq; Ribosome heterogeneity; rRNA 2′O-methylation
    DOI:  https://doi.org/10.1261/rna.081054.126
  43. Trends Genet. 2026 Jun 01. pii: S0168-9525(26)00114-9. [Epub ahead of print]
    Defining cell surface and glycosylated RNAs.
    Eddy Tzintzun-Tapia, Fardin Aryan, Ryan A Flynn.
      The cell surface is a dynamic interface for biomolecular interactions, classically considered to be governed by proteins, lipids, and glycans. Advances in chemical biology and RNA detection have revealed that RNA molecules also reside at the cell surface. We initially identified a class of these resident RNAs as small noncoding RNAs covalently modified with N-glycans, termed glycoRNAs. In this review article, we discuss the technologies that have enabled the identification of glycoRNAs and the more general concept of cell surface RNAs. We also highlight emerging evidence for the trafficking of RNA to the extracellular space and the mechanisms that anchor RNA to the surface of living cells. These observations have reshaped our understanding of RNA regulatory mechanisms and encourage further investigation into previously unrecognized functions of RNAs.
    Keywords:  cell surface; glycoRNA; glycobiology; noncoding RNA; sequencing technologies
    DOI:  https://doi.org/10.1016/j.tig.2026.05.002
  44. Adv Sci (Weinh). 2026 Jun 03. e75895
    Heat Shock Protein 90: From Molecular Chaperone Function to Therapeutic Targeting in Malignancies.
    Beibei Zhang, Xinxin Zou, Jiansong Zhou, Qinmiao Sun, Dahua Chen.
      Heat shock protein 90 (HSP90) is an evolutionarily conserved molecular chaperone that occupies a central position in cellular proteostasis and adaptation to stress. By promoting protein folding and facilitating the functional activation of a broad repertoire of clients, HSP90 underpins essential cellular processes, including development, proliferation, differentiation, and stress responses. In cancer, this extensive network renders tumor cells highly dependent on HSP90 to maintain oncogenic signaling, tolerate proteotoxic stress, and survive therapeutic insults. In this review, we propose an integrated conceptual framework linking HSP90's molecular chaperone functions to its pathological roles in cancer: HSP90 serves as a central node that concurrently supports oncogenic signaling, buffers proteotoxic stress, maintains cancer stem cell plasticity, and shapes tumor-immune interactions-all of which converge to drive therapeutic resistance and tumor recurrence. Within this framework, we summarize the molecular mechanisms governing HSP90 activity and dissect its context-dependent roles in cancer progression, drug resistance, and immune regulation. We further highlight recent advances in HSP90-targeted interventions, including small-molecule inhibitors, monoclonal antibodies, engineered immune cells, and emerging strategies designed to prevent, delay, or overcome drug resistance. Taken together, these developments underscore HSP90 as a versatile therapeutic node and point toward innovative, resistance-aware strategies for clinical translation and future research.
    Keywords:  cancer recurrence; drug resistance; heat shock protein; immunotherapy; molecular chaperone
    DOI:  https://doi.org/10.1002/advs.75895
  45. Biochem Biophys Res Commun. 2026 May 28. pii: S0006-291X(26)00822-3. [Epub ahead of print]827 154058
    RBM46 promotes meiotic initiation during oogenesis.
    Jiawei Li, Jun Shen, Yanqiu Ma, Jian Zhou.
      RNA binding protein RBM46, as an integral component of MEIOC-YTHDC2 complex, governs the RNA binding specificity in posttranscriptional regulation of male meiotic initiation. RBM46 is also indispensable for embryonic oocyte development in mice. However, the precise phenotypic consequences and underlying regulatory mechanisms of RBM46 in female germ cells remain largely uncharacterized. Here, we demonstrate that RBM46 deficiency leads to derepression of CCNA2, meiotic arrest at leptotene stage and widespread germ cell apoptosis in embryonic ovaries. Transcriptomic profiling of RBM46-deficient ovaries at embryonic day 16.5 revealed significant upregulation of Stra8 and Lin28a, alongside downregulation of multiple meiotic genes. In HEK293T cells, ectopic co-expression of RBM46, MEIOC and YTHDC2 promoted degradation of reporter mRNAs bearing either Lin28a or Mga 3'UTR. Notably, Deletion of the RBM46-binding motif "AAUCAU" within Lin28a 3'UTR reduced this repressive effect. Collectively, these findings establish an essential role of RBM46 for meiotic initiation in female germ cells and identify Lin28a and Mga transcripts as direct targets subject to RBM46-mediated decay.
    Keywords:  Female infertility; LIN28A; MGA; Meiotic initiation; Posttranscriptional regulation; RBM46
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154058
  46. bioRxiv. 2026 May 25. pii: 2026.05.21.726964. [Epub ahead of print]
    Single-Cell Translation and Apoptosis Profiling to Define Human CD34 + Cell Response to Specific Factors.
    Dan Li, Karin Gustafsson, Jelena Milosevic, Anna Kiem, David T Scadden.
      Global mRNA translation is a defining functional property of hematopoietic stem cells (HSCs) and is increasingly recognized as a critical axis of dysregulation in myelodysplastic syndromes (MDS) and other clonal hematopoietic disorders. Yet the quantitative measurement of protein synthesis at single-cell resolution across phenotypically defined HSPC subpopulations, in parallel with apoptotic state, is technically challenging. Here we describe and validate a single-tube flow cytometry protocol that simultaneously quantifies global protein synthesis by O-propargyl-puromycin (OP-Puro) incorporation and intracellular cleaved Caspase-3 with cell immunophenotyping across the canonical CD34 + HSPC hierarchy in cryopreserved human cord blood (CB) CD34 + cells. The protocol enables quantitative assessment of key dynamic cell processes in defined subsets of primary hematopoietic cells on a standard flow cytometer. We apply this assay to a four-condition factor-omission analysis of the canonical SR1 + UM729 + dmPGE2 ex vivo expansion cocktail across three independent CB donors. The analysis assigns each compound a distinct functional profile: UM729 constrains protein synthesis and supports apoptotic priming across the hierarchy; SR1 maintains a pro-survival state without modulating translation; and dmPGE2 promotes HSC cycling and progressive exit from the primitive state, with minimal direct effect on the translation or apoptotic axes measured here. This analysis resolves three mechanistically distinct small-molecule signatures using a protocol directly transferable to clinical biobank specimens. We propose it as a functional-state analytic platform that may be useful for patient-derived CD34 + cells from MDS and other myeloid neoplasms in which translational dysregulation is a recognized pathological feature.
    DOI:  https://doi.org/10.64898/2026.05.21.726964
  47. Nat Commun. 2026 Jun 01.
    Cryo-EM reveals multiple mechanisms of ribosome inhibition by doxycycline.
    William S Stuart, Michail N Isupov, Mathew McLaren, Christopher H Jenkins, Adam Monier, Bertram Daum, Isobel H Norville, Vicki A M Gold, Nicholas J Harmer.
      Antimicrobial resistance is driving the search for new antibiotics and a greater understanding of their mechanism of action. Doxycycline is amongst the most-prescribed antimicrobials. It demonstrates a particularly low minimum inhibitory concentration against the zoonotic pathogen Coxiella burnetii. Doxycycline canonically targets the bacterial ribosome by blocking tRNA binding at the decoding centre (A site) of the small subunit. Using cryo-electron microscopy, we analysed doxycycline binding to C. burnetii and Escherichia coli ribosomes. Both structures reveal doxycycline binding at the exit tunnel in the large subunit. In C. burnetii three doxycycline molecules stack to block the tunnel. In E. coli one doxycycline molecule triggers a major change in the conformation of the ribosome. This rearrangement of the peptidyl transferase centre blocks tRNA binding and nascent chain accommodation, abolishing interactions that are fundamental to ribosome function. We identify a distinct ribosomal protein in the C. burnetii large subunit and characterise an additional member of the prokaryotic ribosome hibernation-promoting factor family. These insights into ribosome function and antibiotic action may aid the development of new ribosome inhibitor antibiotics.
    DOI:  https://doi.org/10.1038/s41467-026-73421-5
  48. Cell. 2026 Jun 04. pii: S0092-8674(26)00569-6. [Epub ahead of print]
    Deep learning of functional perturbations from condensate morphology.
    Anita Donlic, Troy J Comi, Sofia A Quinodoz, Nima Jaberi-Lashkari, Krist Antunes Fernandes, Lifei Jiang, Lennard W Wiesner, Ai Ing Lim, Clifford P Brangwynne.
      Biomolecular condensates compartmentalize the interior of cells to organize complex functions, yet linking molecular interactions within condensates to their mesoscale organization remains a major challenge. To bridge this gap, we developed a neural-network-based framework-Deep-Phase (deep learning of phase-separated condensates)-that uses microscopy images to directly measure condensate morphology changes resulting from pharmacological alterations in associated biochemical processes. We use Deep-Phase to precisely quantify time- and concentration-dependent structural perturbations to the multiphase nucleolus and show that they are tightly coupled to potencies of drugs inhibiting ribosomal RNA (rRNA) transcription and processing. Applying Deep-Phase in a chemical screen, we identify a unique nucleolar morphology and discover a role for a DNA topoisomerase in rRNA processing. Mechanistic studies of this morphology provide insights into how the interfaces between nucleolar sub-compartments are maintained. We demonstrate Deep-Phase's adaptability to diverse cell lines, labeling techniques, and condensates, offering a powerful platform for connecting molecular pathways to cellular mesoscale organization.
    Keywords:  RNA biochemistry; RSV; TOP1; biomolecular condensate; deep learning; high-content imaging; morphological profiling; nuclear speckle; nucleolus
    DOI:  https://doi.org/10.1016/j.cell.2026.05.010
  49. bioRxiv. 2026 May 21. pii: 2026.05.18.726057. [Epub ahead of print]
    Neutrophils repurpose the nucleolus as a cytokine reservoir and secretory organelle.
    Shuying Xu, Asya Smirnov, Rachel L Kinsella, Ananda Rankin, Ashley D Wise-Mitchell, Jessica M Alexander, Benjamin Patty, Sophie M Mikhail, Rachel M Bello, Darren Kraemalmeyer, Sebastian Boluarte, Aamir Khan, Benjamin L Allsup, Sheikh Mahmud, Bryan D Bryson, Joshua T Mattila, Eric L Greer, Siyuan Ding, Regina A Clemens, Andrew J Monteith, Eliezer Calo, Christina L Stallings.
      Type I interferons (IFN-I) are critical for antiviral defense but can drive severe pathology when dysregulated. Excess IFN-I is associated with prominent neutrophil accumulation; however, the contribution of neutrophils to IFN-I overproduction remains underexplored. In all cell types previously studied, IFN-I is synthesized de novo following sensing of microbial or host-derived inflammatory stimuli. Contrary to this paradigm, we find that neutrophils express IFNα during development and store it in the nucleolus, a membrane-less intranuclear condensate classically functioning in ribosome biogenesis. TLR-mediated bacterial sensing induces a nucleolar stress response in neutrophils that triggers rapid release of nucleoli-stored IFNα independent of de novo protein synthesis. These findings reveal that neutrophils have repurposed the nucleolus as a cytokine storage and secretory organelle, identify the first naturally occurring immunoregulatory function of nucleolar stress, and provide insight into the relationship between detrimental IFN-I levels and neutrophil accumulation.
    DOI:  https://doi.org/10.64898/2026.05.18.726057
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