bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–06–14
fifty-five papers selected by
Cédric Chaveroux, CNRS
  1. Enhancement of Therapeutic mRNA Translation in Cellular Stress Conditions.
  2. Human RNA ligase 1 as a novel regulator of ribosome function and translation under oxidative stress.
  3. The RNA exosome: mechanisms of RNA surveillance, regulation, and disease.
  4. Glutamine-Linked Cellular Stress Responses in Viral Infection: Mechanisms, Crosstalk, and Future Perspectives.
  5. Observing intersubunit dynamics in single yeast ribosomes.
  6. The host DHX29 RNA helicase regulates HCMV immediate-early protein synthesis.
  7. Coordinated regulation of mRNA translation and stability by ZC3H7A and ZC3H7B RNA-binding proteins.
  8. The regulation of Xrp1 expression by uORFs and main ORF sequences and its function in Drosophila disease models.
  9. Synphilin-1 mitigates autophagy dysfunction, modulates ubiquitinated protein aggregation, and promotes cell survival during proteotoxic stress.
  10. Mutant KRAS-driven selective mRNA translation reveals mechanisms and therapeutic vulnerabilities in cancer.
  11. The Translatome of Senescent Cells Revealed by Sequencing Actively Translated mRNA.
  12. Transcripts enriched in codons that trigger P-site tRNA-mediated mRNA decay possess stable mRNA.
  13. A Microscale Platform for the Comprehensive Analysis of Bacterial Translation Initiation.
  14. Effect of transcriptional delay on ribosome abundance control.
  15. The relevance of m6A RNA modifications in cancer stem cells.
  16. eIF3 Orchestrates a Biphasic Stress Response Linking Translational Control to Mitochondrial Integrity in Skeletal Muscle.
  17. The integrated to developmental stress response (ISR-DASR) shift reveals a functional transition from cellular to stem cell organismal adaptation.
  18. RNA Polymerase III subunit Polr3a is required for craniofacial cartilage and bone development in zebrafish.
  19. Nucleoplasmic checkpoint of the 40S ribosomal decoding center maturation.
  20. Integrated Stress Response and Necroptosis Drive Epithelial Dysfunction in Crohn's Disease: Repurposing Cancer Drugs for Permeability Barrier Healing.
  21. FTO-mediated m6A demethylation of BCL6 promotes gastric cancer progression by suppressing ferroptosis.
  22. A long non-coding RNA, afu-254, is required for the oxidative stress response, cell wall stress response, azole susceptibility, and virulence in Aspergillus fumigatus.
  23. Structural basis of long-range transcription-translation coupling.
  24. Ribosome Biogenesis as a Putative Bottleneck to Skeletal Muscle Hypertrophy: Mechanisms, Human Evidence, and Practical Modulators.
  25. Conserved RNA helicase Vasa regulates ribonucleoprotein condensate dynamics and mRNA localization.
  26. Ribosomal allostery as a potential regulator of bacterial dormancy.
  27. Emerging perspectives in proteostasis: bridging mechanisms and therapeutics for human diseases.
  28. Biomolecular Condensates in Plant Stress and Development: Recent Advances and Emerging Concepts.
  29. The importance of nonsense errors: Estimating the rates and implications of ribosome drop-off during protein synthesis.
  30. The assembly of stress granules during foot-and-mouth disease virus infection is uncoupled from activation of cellular intrinsic antiviral signalling.
  31. Structural insights into YheS-mediated release of SecM-arrested ribosome.
  32. TRNAU1AP and PRPF39 establish integrated control over processing of most abundant human non-coding RNAs.
  33. AMPK tunes reproductive gene expression and small RNA homeostasis to mediate timely germ cell development.
  34. Human J-domain proteins promote stress granule disassembly and suppress neurodegeneration-linked protein aggregation.
  35. Altered translation efficiency of specific mRNAs in a zebrafish model of Diamond-Blackfan anemia syndrome.
  36. High-throughput screening identifies a critical role of the SPOP-PABPC1 axis in lung adenocarcinoma progression.
  37. Understanding the OMA1-DELE1-HRI Axis and PINK1-parkin-mediated Mitophagy in Parkinson's Disease.
  38. mRNA 3' UTRs chaperone intrinsically disordered regions to control protein activity.
  39. Enhancing targeted strategies for cancer immunotherapy by elucidating mRNA processing mechanisms.
  40. Pancreatic β-Cell Aging in Physiology and Diabetes: Emerging Roles of m6A mRNA Methylation.
  41. IGF2BP3 promotes epithelial ovarian cancer progression by regulating FASN expression.
  42. A 3'UTR polymorphism disrupts IRF2BP2 autoregulation through an eIF4H translational enhancer.
  43. A transfer RNA inosine modification drives genome-wide synonymous recoding across human commensal bacterial families.
  44. Heme orchestrates a tissue stress response to proteolytic damage.
  45. A RiboCancer cell line panel reveals that CLL-associated Rps15 mutations translationally rewire transcription through codon-specific tRNA accommodation defects.
  46. m6A-modified ATF4 regulates glucose/lipid metabolism via the Sestrin2/GSK3β axis to alleviate myocardial ischemia-reperfusion injury.
  47. From energy provision to protein synthesis: Tunnelling nanotubes as mediators of intercellular metabolic cooperation in cancer.
  48. Exploring the organismal role of UFMylation in development, stress resilience and neurological function in C. elegans.
  49. Systematic Mapping of Protein Interactions Underlying IL-2 Secretion in Human T Cells.
  50. Molecular Evolution of the Archaeal DNA-Dependent RNA Polymerase: Cooperative Changes in Subunit Composition and Specific Domains of Small Subunits.
  51. Role of G3BP1 phosphorylation in the regulation of plant immunity in Arabidopsis thaliana.
  52. ALKBH5 promotes the progression of cisplatin-resistant oral squamous cell carcinoma by regulating FOXA1 expression via m6A RNA methylation : Funding.
  53. Excess copper causes repression of global translation in Saccharomyces cerevisiae.
  54. Quercetin Affects Carcinogenic Phenotype of Breast and Lung Cancer Cells Differentially Through Sterol Regulation Mediated by MALAT1 Perturbation.
  55. IDH1-Associated m6A Methylation Is Linked to Transcriptomic Heterogeneity in Glioma.
  1. Int J Mol Sci. 2026 May 22. pii: 4663. [Epub ahead of print]27(11):
    Enhancement of Therapeutic mRNA Translation in Cellular Stress Conditions.
    Edyta Trepkowska-Mejer.
      This review summarizes mechanisms regulating mRNA translation under cellular stress and highlights design strategies to improve translation efficiency and stability in the gene therapy of human diseases. mRNA-based therapeutics are emerging as a versatile gene therapy platform enabling transient and controllable expression of therapeutic proteins for the treatment of cancer, genetic disorders, and inflammatory diseases. The efficacy of mRNA-based gene therapy is strongly influenced by sequence design, chemical modifications, and structural features. Evidence shows that rational mRNA engineering can significantly enhance translation efficiency even under stress conditions that impair canonical protein synthesis, as observed in many pathological states. Cellular stress activates regulatory pathways that suppress global translation; however, optimized mRNA constructs can partially bypass these inhibitory mechanisms, enabling sustained protein expression. By improving mRNA stability and resistance to stress-responsive translational control, robust therapeutic protein production can be achieved even in challenging cellular environments. This article was prepared as a narrative review focused on translational regulation mechanisms relevant to therapeutic mRNA design under cellular stress conditions. Literature was collected from PubMed, Google Scholar, and Web of Science using keywords including "mRNA therapeutics," "cellular stress," "translation regulation," "UTR engineering," and "cap-independent translation." Studies published mainly between 2010 and 2025 were considered. Original articles and reviews related to stress-responsive translation and therapeutic mRNA optimization were included, while studies outside the scope of translational control and mRNA engineering were excluded. Priority was given to recent and mechanistically relevant publications.
    Keywords:  alternative translation; cellular stress; innovative therapy; mRNA design; mRNA therapeutics
    DOI:  https://doi.org/10.3390/ijms27114663
  2. Nucleic Acids Res. 2026 Jun 08. pii: gkag528. [Epub ahead of print]54(11):
    Human RNA ligase 1 as a novel regulator of ribosome function and translation under oxidative stress.
    Florian Michael Stumpf, Marissa Glauner, Jasmin Jansen, Virginie Marchand, Yuri Motorin, Florian Stengel, Andreas Marx.
      Human RNA ligase 1 (Rlig1) is a recently identified human 5'-3' RNA ligase required for maintaining 28S ribosomal RNA integrity and promoting cell survival under oxidative stress. Although its enzymatic activity suggests a role in RNA processing and repair, the broader molecular context of Rlig1 remains poorly defined. Here, we identified potential Rlig1-associated proteins by affinity enrichment-mass spectrometry. Subsequent analysis revealed proteins involved in RNA surveillance and processing, including RNA-binding and end-processing enzymes, and indicated strong enrichment of ribosomal proteins. We showed that Rlig1 interacts with 80S ribosomes in vitro. Consistent with this observation, polysome profiling revealed recruitment of Rlig1 to ribosomal fractions under oxidative stress. Functionally, Rlig1-knockout (KO) HEK293 cells exhibited accelerated polysome loss and significantly reduced global protein synthesis compared to wild-type (WT) HEK293 cells during oxidative stress. In addition, we showed that stress-induced RNA fragments containing a 5'-PO4 end accumulated in Rlig1-KO cells. Among these, transfer RNA halves were prominently enriched. Together, our study links Rlig1 to ribosomal complexes and suggests that Rlig1 contributes to preserving RNA integrity and supporting translational capacity during oxidative stress.
    DOI:  https://doi.org/10.1093/nar/gkag528
  3. RNA Biol. 2026 Dec 31. 23(1): 1-24
    The RNA exosome: mechanisms of RNA surveillance, regulation, and disease.
    Priyanka Upadhyai, Neha Quadri, Divya Chandran.
      The RNA exosome is a conserved multi-subunit ribonuclease complex with pivotal roles in RNA biogenesis, surveillance, and processing. It comprises a nine-subunit scaffold that associates with distinct ribonucleases in a cell compartment-specific manner, contributing to the processing and turnover of a broad spectrum of nuclear and cytoplasmic transcripts, including pervasively transcribed and short-lived RNAs, precursors, and abortive and aberrant transcripts. In this review, we examine how the RNA exosome engages a wide spectrum of RNAs via differential adaptor usage and intrinsic substrate features, such as transcript length and 3' end structure. This also modulates the entry routes of the recruited transcripts. We highlight conserved principles and major differences between yeast and metazoans. We assimilate emerging evidence that suggests that the RNA exosome localization and activity are dynamically regulated in response to cellular context and external stimuli. Finally, drawing on findings from studies in S. cerevisiae, Drosophila, zebrafish, and mice, we discuss how perturbations in RNA surveillance can result in abnormalities in organismal development and homoeostasis. Together, these studies not only enhance our knowledge of the broader relevance of RNA quality control and metabolism but also provide mechanistic insights into pathomechanisms, particularly the tissue-specific vulnerabilities noted in RNA exosome-linked diseases.
    Keywords:  RNA exosome; RNA exosome cofactors; RNA exosomopathies; RNA quality control; RNA surveillance
    DOI:  https://doi.org/10.1080/15476286.2026.2685379
  4. Int J Mol Sci. 2026 May 23. pii: 4717. [Epub ahead of print]27(11):
    Glutamine-Linked Cellular Stress Responses in Viral Infection: Mechanisms, Crosstalk, and Future Perspectives.
    Ngan Thi Kim Pham, Quang Duy Trinh, Hiroshi Ushijima, Shihoko Komine-Aizawa, Kazuaki Yoshimune.
      Glutamine is the most abundant amino acid in human plasma and tissues and plays essential roles in cellular metabolism, biosynthesis, and redox homeostasis. Beyond these canonical functions, glutamine availability and utilization have emerged as key regulators of multiple cellular stress responses, including the integrated stress response, endoplasmic reticulum stress, metabolic checkpoint signaling, and autophagy. During viral infection, host glutamine metabolism is frequently reprogrammed to meet the energetic and biosynthetic demands of viral replication, thereby inducing or reshaping glutamine-linked stress pathways. Increasing evidence indicates that these stress responses are not merely secondary consequences of infection but actively influence key stages of the viral life cycle, including viral entry, genome replication, protein synthesis, and host antiviral responses. In this review, we summarize current advances in understanding how glutamine metabolism regulates cellular stress responses in the context of both viral and non-viral infections, and how these pathways, in turn, modulate viral pathogenesis and host defense. We discuss the context-dependent roles of glutamine-linked stress signaling in either promoting viral replication or restricting infection, depending on viral species, host cell type, and metabolic conditions. Finally, we highlight emerging concepts and unresolved questions, including the potential of targeting glutamine metabolism and associated stress pathways as host-directed antiviral strategies. A deeper understanding of the interplay between glutamine metabolism, cellular stress responses, and viral infection may provide new insights into disease mechanisms and inform the development of novel therapeutic approaches.
    Keywords:  ER stress; autophagy; cellular stress response; glutamine metabolism; integrated stress response (ISR); metabolic stress; oxidative stress; viral entry; viral replication; virus–host interactions
    DOI:  https://doi.org/10.3390/ijms27114717
  5. Nucleic Acids Res. 2026 Jun 08. pii: gkag576. [Epub ahead of print]54(11):
    Observing intersubunit dynamics in single yeast ribosomes.
    Ananya Das, Amy K Grove, Aleksandr V Ivanov, Hironao Wakabayashi, Dmitri N Ermolenko.
      Translation is accompanied by the rotation of the small and large ribosomal subunits relative to each other. Here, we use single-molecule Förster resonance energy transfer between fluorophores introduced into ribosomal proteins uS15 and eL30 to follow the intersubunit dynamics of Saccharomyces cerevisiae ribosomes. Similar to their bacterial counterparts, yeast ribosomes are observed to sample two predominant FRET states corresponding to the nonrotated (NR) and rotated (R) conformations. Our data yield further evidence that intersubunit rotation is coupled to tRNA transitions between the classical and hybrid binding states. The elongation cycle, which comprises tRNA binding, peptide transfer, and mRNA-tRNA translocation, is accompanied by switching from NR to R, and then back to the NR conformation. We find that fungal elongation factor 3 (eEF3) stabilizes the NR conformation of the ribosome. Our data are consistent with the model suggesting that eEF3 facilitates E-site tRNA release at the late step of mRNA-tRNA translocation, following the reverse intersubunit rotation induced by the universally conserved elongation factor 2 (eEF2). Our uS15-eL30 smFRET assay provides the basis for investigating eukaryotic mechanisms of translation regulation, including ribosome pausing, stalling, and frameshifting.
    DOI:  https://doi.org/10.1093/nar/gkag576
  6. mBio. 2026 Jun 09. e0354225
    The host DHX29 RNA helicase regulates HCMV immediate-early protein synthesis.
    Erik M Lenarcic, Nathaniel J Moorman.
      The DEAD-box helicase DHX29 plays a critical role in the translation of mRNAs containing complex RNA secondary structure in their 5' untranslated regions (UTRs). The human cytomegalovirus (HCMV) genome has a high GC content, suggesting that the 5' UTRs of viral mRNAs may contain significant secondary structure and require DHX29 for efficient translation. We found that depleting DHX29 from primary human fibroblasts prior to infection reduced viral mRNA and protein levels and decreased HCMV replication. The defect in HCMV replication correlated with decreased expression of the HCMV immediate-early proteins IE1 and IE2, which are necessary for the establishment of lytic infection. Analysis of polysome-associated mRNAs revealed that the defect in IE1 and IE2 expression is due to decreased mRNA translation efficiency. DHX29 depletion led to reduced levels of the eIF4F translation initiation complex, resulting from decreased translation of the eIF4G1 mRNA. However, in line with our previous results showing a minimal role for the eIF4F complex in viral mRNA translation, we found that depleting eIF4G prior to infection did not impact IE1 and IE2 translation. Together, our results define a new role for DHX29 in regulating eIF4F-dependent translation and identify a critical role for DHX29 in the translation of HCMV mRNAs.
    IMPORTANCE: Expression of the human cytomegalovirus (HCMV) immediate-early proteins IE1 and IE2 is critical for the establishment of lytic replication and the reactivation of latent HCMV infections. Defining the mechanisms controlling HCMV IE1 and IE2 protein expression has the potential to identify new strategies for therapeutic interventions that can limit HCMV disease in immune-naïve and immune-compromised individuals. Our finding that the cellular DHX29 helicase is necessary for the efficient translation of mRNAs encoding IE1 and IE2 suggests that therapies that inhibit DHX29 could potentially be useful in treating HCMV disease and adds to the growing body of literature suggesting that DHX29 activity is a disease driver in multiple indications, including viral disease, inflammation, and cancer.
    Keywords:  HCMV; RNA binding proteins; RNA helicase; human cytomegalovirus; human herpesvirus; lytic replication; mRNA translation; major immediate early gene; protein synthesis
    DOI:  https://doi.org/10.1128/mbio.03542-25
  7. Cell Rep. 2026 Jun 09. pii: S2211-1247(26)00589-9. [Epub ahead of print]45(6): 117511
    Coordinated regulation of mRNA translation and stability by ZC3H7A and ZC3H7B RNA-binding proteins.
    Patric Harris Snell, Parisa Naeli, Aitor Garzia, Yanyu Chen, Joseph A Waldron, Susanta Chatterjee, Tom McGirr, Aidan Kilmartin, Eman Suleiman Mohammad Almomani, Ian R Kelsall, Reese Jalal Ladak, Jung-Hyun Choi, Jun Luo, Sami A Leino, Naomi Jess, S Ali Shariati, Ximena Soto, Christos G Gkogkas, Nahum Sonenberg, Thomas Tuschl, Sarah Maguire, Seyed Mehdi Jafarnejad.
      mRNA translation and stability are tightly regulated and functionally linked through cis-acting sequence elements and trans-acting factors, including RNA-binding proteins (RBPs). Here, we report that two chordate-specific paralogous RBPs, ZC3H7A and ZC3H7B, preferentially bind the coding region (CDS) and 3' untranslated region (3' UTR) of A/U-rich mRNAs, particularly those with enrichment of A/U at their wobble sites (A/U3 codons). Upon binding to target mRNAs, ZC3H7A/B promote mRNA degradation through recruitment of the CCR4-NOT deadenylase complex. Furthermore, these proteins engage ribosomes lacking elongation factors and repress translation initiation via the GIGYF2/4EHP translation repressor complex. Depletion of ZC3H7A/B or 4EHP impairs the translational repression of A/U3-rich mRNAs. Together, these findings reveal a mechanism in higher eukaryotes that links A/U-rich sequence content within the CDS and 3' UTR to the coordinated post-transcriptional regulation of mRNA stability and translation.
    Keywords:  3′ untranslated region; 4EHP; CP: molecular biology; GIGYF2; ZC3H7A; ZC3H7B; codon content; eIF4E2; mRNA decay; mRNA translation; non-optimal codons
    DOI:  https://doi.org/10.1016/j.celrep.2026.117511
  8. PLoS Genet. 2026 Jun 10. 22(6): e1012203
    The regulation of Xrp1 expression by uORFs and main ORF sequences and its function in Drosophila disease models.
    Hidetaka Katow, Thao Nguyen, Sarah Hyunsoh Park, Hyung Don Ryoo.
      The Integrated Stress Response (ISR) mediates cellular adaptation to endoplasmic reticulum (ER) stress, amino acid deprivation, and mitochondrial dysfunction. The ISR regulates gene expression in part by preferentially translating the transcription factor ATF4, a process regulated by upstream open reading frames (uORFs) in its 5' leader. In Drosophila, Xrp1 is another transcription factor induced during the ISR, but the precise underlying mechanism remains unclear. Here, we report that Xrp1 induction in response to ER stress is regulated by both its uORFs and the main ORF sequence. Xrp1 has seven splice isoforms, and the two predominant transcripts expressed in eye imaginal discs contain uORFs. Expressing the ER stress-imposing ninaEG69D transgene in this tissue induced Xrp1 expression without significantly changing the Xrp1 splice isoform composition. The uORF-containing 5' leaders, particularly the AUG codon of the second uORF, inhibited DsRed expression when placed upstream of the reporter. Unlike ATF4, the uORF-containing 5' leader alone was insufficient to mediate the main ORF induction, but Xrp1 induction occurred in ninaEG69D-expressing discs when Xrp1's 5' leader and the main ORF sequence were both present. Functionally, Xrp1 was required to maintain the integrity of Drosophila photoreceptors exposed to constant light. In a different disease model, parkin mutants activated Xrp1 target gene expression in specific tissues and Xrp1 loss enhanced the viability of parkin mutant flies during adult eclosion. These results provide molecular and pathological insights into Xrp1 regulation and function in disease models.
    DOI:  https://doi.org/10.1371/journal.pgen.1012203
  9. bioRxiv. 2026 Jun 02. pii: 2026.05.31.729136. [Epub ahead of print]
    Synphilin-1 mitigates autophagy dysfunction, modulates ubiquitinated protein aggregation, and promotes cell survival during proteotoxic stress.
    Nadine M Lebek, Kenneth G Campellone.
      The decline of cellular proteostasis is a hallmark of aging and key contributor to neurodegenerative diseases. Protein turnover is controlled by the ubiquitin-proteasome and autophagosome-lysosome systems, but how degradation is coordinated when one of these pathways is compromised is not well understood. To study the regulation of proteostasis, we utilized human fibroblasts with targeted knockouts of the cytoskeletal factors WHAMM and JMY, which control multiple steps in autophagy. We found that cells lacking both WHAMM and JMY accumulated numerous intense foci of ubiquitinated proteins when exposed to proteotoxic stress and relied on proteasomes to clear the foci when the stressor was removed. RNA-seq and immunoblotting revealed that WHAMM/JMY knockout cells increased their expression of Synphilin-1, an α-synuclein-interacting protein implicated in Parkinson's Disease. In WHAMM/JMY knockout cells that upregulated endogenous Synphilin-1, and in cell lines engineered to overexpress mCherry-Synphilin-1, ubiquitinated proteins were present in structures containing both Synphilin-1 and proteasomes. RNAi-mediated depletion of Synphilin-1 caused a buildup of ubiquitinated proteins and the ubiquitin-binding adaptor protein SQSTM1/p62, while decreasing cell survival in response to proteotoxic stress. These data suggest that Synphilin-1 plays a pro-survival role in cells with impaired autophagy and functions in the distribution of ubiquitinated cargo during proteasomal degradation.
    DOI:  https://doi.org/10.64898/2026.05.31.729136
  10. Cell Rep. 2026 Jun 11. pii: S2211-1247(26)00598-X. [Epub ahead of print]45(6): 117520
    Mutant KRAS-driven selective mRNA translation reveals mechanisms and therapeutic vulnerabilities in cancer.
    Ankita Shrivastava, Eric Nels Pederson, Trang Uyen Nguyen, Jacky Chuen, Prathibha Mohan, Shivangi Pande, Ana Ruiz Toribio, Nicolas Lecomte, Jerry Melchor, John C McAuliffe, Paul M Grandgenett, Vinagolu K Rajasekhar, Kaila Nishikawa, Anna Knörlein, Yael David, Ian M Willis, Christine A Iacobuzio-Donahue, Zhengqing Ouyang, Kamini Singh.
      Mutant KRAS-driven control of protein synthesis remains poorly defined. Here, we define KRAS-dependent translational programs and their acute remodeling upon KRAS inhibition. We find that mutant KRAS controls the translation of a subset of mRNAs and affects the production of proteins of the mRNA translation apparatus. Interestingly, these specific subsets of mRNAs have short, weakly folded 5'UTRs and harbor low folding energy consensus RNA sequences. We observe ribosome accumulation on selective mRNAs. Our findings clarify the indispensable role of mutant KRAS in regulating mRNA translation, setting it apart from the other previously known mechanisms that depend on mTOR and EIF4E-EIF4A signals. Our findings uncover a mechanism by which mutant KRAS selectively uncouples the translation of mRNAs for protein synthetic machinery from the broader mRNA pool, redefining our understanding of the oncogenic regulation of mRNA translation in cancer.
    Keywords:  CP: cancer; CP: molecular biology; EEF1A; EIF4A; KRAS inhibitors; Ribosome; mRNA translation; mTOR signaling; mutant KRAS; oncogenic signaling; ribosome profiling; ribosome stalling, pancreatic cancer
    DOI:  https://doi.org/10.1016/j.celrep.2026.117520
  11. bioRxiv. 2026 Jun 07. pii: 2026.02.27.708233. [Epub ahead of print]
    The Translatome of Senescent Cells Revealed by Sequencing Actively Translated mRNA.
    Maxfield M G Kelsey, Radha L Kalekar, John M Sedivy.
      Cellular senescence drives aging-related tissue dysfunction through the senescence-associated secretory phenotype (SASP), an inflammatory secretome linked to retrotransposable element (RTE) derepression. Transcriptomic and proteomic approaches have extensively characterized the senescence program, but key gaps remain: transcript abundance is a poor proxy for protein output, limited proteomic depth misses low-abundance proteins, and the highly repetitive sequences of RTEs compromise locus-level peptide attribution. To bridge these gaps, we used AHARIBO (AzidoHomoAlanine-mediated RIBOsome isolation), which captures actively translated full-length mRNAs, to profile the translatome of proliferating, senescent, and late senescent human fibroblasts. Comparing these ribosome-associated transcripts with the total mRNA pool revealed marked post-transcriptional regulation of key senescence programs. Inflammatory SASP components were translationally depleted in senescence and these transcripts are enriched for AU-rich element-binding protein motifs, including the ZFP36 family, implicating these proteins in post-transcriptional gating of inflammatory signaling. Transcriptome-wide, translational efficiency was associated with 3'UTR GC content and specific RNA-binding protein and microRNA (miRNA) motifs. We also observed a striking wobble-position codon bias: a proliferation-specific program favoring A/U-ending codons collapses in senescence, disproportionately affecting cell-cycle and proliferation gene sets. By pairing AHARIBO with a sample-specific reference genome incorporating non-reference L1 insertions, we resolved translation of individual L1 loci and identified two intact L1HS elements with sustained activation in senescence. One of these, L1HS_14q23.2_3, independently identified in multiple experiments, emerges as a candidate intact L1 locus for producing inflammatory cDNA species. These findings establish translational control as an important regulatory layer shaping the senescent program.
    DOI:  https://doi.org/10.64898/2026.02.27.708233
  12. FEBS Open Bio. 2026 Jun 12.
    Transcripts enriched in codons that trigger P-site tRNA-mediated mRNA decay possess stable mRNA.
    Rodolfo Lopes Carneiro, Fernando Lucas Palhano.
      Synonymous codon usage significantly influences mRNA stability in yeast by guiding mRNA decay during translation. The CCR4-NOT complex is central to this process, interacting with ribosomes when the A and E sites are unoccupied, a state that arises when a nonoptimal codon with low tRNA availability is at the A site. This triggers recruitment of decay factors, reducing the stability of transcripts enriched in such codons. In humans, codon-mediated mRNA decay is less well-understood. Recent research has identified a related but distinct mechanism called P-site tRNA-mediated decay (PTMD). Unlike yeast, human CCR4-NOT recruitment depends on specific arginine codons (CGG, CGA, or AGG) at the P site and slow decoding at the A site, allowing E-site vacancy and CNOT3-dependent binding. Through analysis of public datasets, we explored the characteristics of human transcripts enriched in PTMD codons. Interestingly, these codons are mostly found in transcripts with longer half-lives. This suggests that, rather than targeting already unstable mRNAs as in yeast, PTMD in humans selectively reduces the stability of otherwise long-lived transcripts, indicating a regulatory role distinct from the decay associated with codon usage.
    Keywords:  Translation; codon usage; mRNA decay; mRNA turnover; tRNA
    DOI:  https://doi.org/10.1002/2211-5463.70277
  13. Int J Mol Sci. 2026 May 29. pii: 4953. [Epub ahead of print]27(11):
    A Microscale Platform for the Comprehensive Analysis of Bacterial Translation Initiation.
    Daria S Vinogradova, Pavel S Kasatsky, Zoya A Spiridonova, Sebastian Leyva, Ana Sanchez-Castro, Katherin Peñaranda, Victor Zegarra, Pablo Soriano, Alena Paleskava, Pohl Milon, Andrey L Konevega.
      In prokaryotes, translation initiation orchestrates protein synthesis through a network of dynamic interactions among the ribosome, mRNA, initiator tRNAfMet, and initiation factors (IFs). Traditional approaches that rely on radioactive labeling or surface immobilization are hindered by inherent safety risks and methodological constraints. We present a fluorescence-based analytical platform that integrates microscale thermophoresis (MST) as a unified, multiparametric toolkit for comprehensive interrogation of bacterial translation initiation at the molecular level. By systematically applying MST to a panel of fluorescently labeled components-initiator tRNAfMet, mRNAs, and initiation factors-we quantify assembly pathways and equilibria as initiation progresses from simple bimolecular interactions to higher-order, multicomponent complexes. To broaden the fluorescence toolbox for ribosomal studies, we developed a robust BODIPY-labeling protocol for 70S ribosomes and confirmed preservation of structural integrity and function by nano differential scanning fluorimetry, stopped-flow kinetic assays, and peptide-synthesis activity tests. Our microscale fluorescent system facilitates probing initiation at a variety of steps, since the role of magnesium ions and initiation factors upon 30S initiation complex formation. The same platform can be applied to investigate the effects of different compounds on translation initiation, as demonstrated for a number of antibiotics, aptamers, and antimicrobial peptides. Using this approach, we determined the antibiotic streptomycin dissociation constant for both 30S and 70S ribosomes, which proved identical at 0.3 ± 0.1 μM, and demonstrated the effect of the antimicrobial peptide rumicidin-1 on translation initiation. Offering a cost-effective and high-sensitivity alternative to conventional methods, this approach advances mechanistic understanding of prokaryotic translation and provides a versatile framework for the discovery of novel protein synthesis inhibitors.
    Keywords:  antibiotics; antimicrobial peptides; fluorescence; microscale thermophoresis; nano differential scanning fluorimetry; prokaryotic translation initiation; protein synthesis inhibitors; ribosome assembly
    DOI:  https://doi.org/10.3390/ijms27114953
  14. J Math Biol. 2026 Jun 12. pii: 2. [Epub ahead of print]93(1):
    Effect of transcriptional delay on ribosome abundance control.
    Pavan C Perera, Sergei S Pilyugin, Lisa Davis, Tomas Gedeon.
      Time delays are inherent in biological processes such as transcription and translation, and they play a vital role in cellular control by altering timing of feedback loops and therefore stability of steady states. Standard ordinary differential equation (ODE) models neglect these delays, potentially eliminating important dynamic behavior. We present a mathematical model that explores the synthesis of ribosomal proteins and their mRNA in E. coli using both ODE and delay differential equation (DDE) models. Comparing these two models we discover that, while there can only be two equilibrium states in both the ODE and the DDE systems, the addition of delays destabilizes the internal equilibrium via the Hopf bifurcation, resulting in oscillatory dynamics. We show that there are parameter combinations where two stable periodic orbits coexist, and one of them terminates in a torus bifurcation giving rise to a stable torus of recurrent orbits. The existence of oscillatory behavior is consistent with experiments.
    Keywords:  DDE-BIFTOOL; Delay differential equations; Hopf bifurcation; Ribosome abundance
    DOI:  https://doi.org/10.1007/s00285-026-02420-3
  15. J Cancer Res Clin Oncol. 2026 Jun 09.
    The relevance of m6A RNA modifications in cancer stem cells.
    Alexandra Monteiro, Diana Pádua, Catarina Gonçalves, Patrícia Mesquita, Raquel Almeida.
      Cancer is a multifactorial disease, driven by dysregulation of cellular processes that are controlled by the complex influence of DNA and RNA-level regulatory mechanisms. Epitranscriptomics has surfaced as a prominent field in cancer research, providing a clearer understanding of post-transcriptional regulation of gene expression. In particular, N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic mRNA, and has emerged as a key regulator of post-transcriptional gene expression. Through the coordinated activity of methyltransferases ("writers"), demethylases ("erasers") and binding proteins ("readers"), m6A dynamically modulates important RNA processing steps, including translation, stability, decay and splicing. Notably, m6A regulatory proteins are implicated in several stemness pathways acting as oncogenic drivers or tumor suppressors in a highly context-dependent manner. This regulatory flexibility is particularly relevant in cancer stem cells (CSCs), a highly plastic subpopulation involved in tumor initiation, progression, metastasis and therapy resistance. Indeed, some of the major challenges in oncology arise from cancer cell adaptability, tumor heterogeneity and microenvironment-dependent outcomes, processes in which m6A emerges as a critical regulatory layer. This review summarizes the mechanisms of m6A regulation and its biological effects, and provides an overview of the influence of m6A in CSC phenotypes. Finally, it explores how m6A affects therapeutic responses, future perspectives in oncology and the key challenges currently under investigation in this field.
    Keywords:  cancer metabolism; cancer stem cells; cellular plasticity; epitranscriptomics; m6A; therapy resistance
    DOI:  https://doi.org/10.1007/s00432-026-06525-6
  16. FASEB J. 2026 Jun 30. 40(12): e71972
    eIF3 Orchestrates a Biphasic Stress Response Linking Translational Control to Mitochondrial Integrity in Skeletal Muscle.
    Yingying Lin, Jianing Xia, Man Li, Junhao Zhang, Yonghao Mu, Lenian Ling, Minghao Lu, Jiahuan Wang, Kexin Liao, Yefeng Cai.
      Skeletal muscle adaptation to physiological and pathological stressors requires precise coordination of protein synthesis and mitochondrial function. While the roles of canonical translation regulators such as eIF2α and 4E-BP1 in exercise-induced protein synthesis modulation are well established, the contribution of eIF3, the largest eukaryotic initiation factor complex, to muscle stress responses remains poorly understood. Eukaryotic initiation factor 3 (eIF3) regulates mRNA translation and mitochondrial homeostasis, yet how individual eIF3 subunits respond to distinct modes of skeletal muscle stress remains unclear. Here, we systematically characterized eIF3 dynamics and mitochondrial function using two complementary mouse models: acute exhaustive training and dexamethasone (DEX)-induced atrophy. Integrated proteomic, transcriptional, and imaging analyses revealed a biphasic regulatory pattern: DEX treatment caused broad downregulation of eIF3a, eIF3b, eIF3c, eIF3g, and eIF3l, concurrent with comprehensive mitochondrial electron transport chain (ETC) impairment, while acute training selectively decreased eIF3d, eIF3e, eIF3g, and eIF3l but uniquely preserved eIF3f expression alongside adaptive ETC remodeling. This differential response pattern distinguishes eIF3 from other stress-responsive translation factors, as eIF2α phosphorylation typically causes global translation suppression whereas eIF3 dysregulation selectively impairs mitochondrial protein synthesis. Notably, eIF3f preservation under both conditions suggests a compensatory mechanism to maintain translational capacity. siRNA-mediated knockdown of eIF3e or eIF3f in C2C12 myotubes demonstrated their differential effects on mitochondrial protein expression and atrophy signaling, with eIF3f knockdown causing more severe mitochondrial protein suppression. Seahorse XF analysis confirmed that eIF3 subunit loss directly impairs mitochondrial oxygen consumption, while SUnSET assays demonstrated attenuated global protein synthesis upon eIF3e or eIF3f depletion. Furthermore, eIF3 knockdown suppressed mTORC1 signaling (p-mTOR, p-4EBP1, p-S6K, p-S6) and differentially modulated ubiquitin-proteasome activity without altering bulk autophagy. These findings establish eIF3 as a molecular integrator linking translational control to mitochondrial integrity in skeletal muscle physiology, positioning this complex as a potential therapeutic target for conditions ranging from exercise-induced adaptation to muscle wasting disorders.
    Keywords:  ETC complex; eIF3; mitochondria; muscle adaptation; skeletal muscle; translation regulation
    DOI:  https://doi.org/10.1096/fj.202600161R
  17. Sci Rep. 2026 Jun 10.
    The integrated to developmental stress response (ISR-DASR) shift reveals a functional transition from cellular to stem cell organismal adaptation.
    Ximena Ruden, Campbell Coddington, Lynessa Asplund, Awoniyi Awonuga, Douglas Ruden, Steven Korzeniewski, Lijun Zhang, Elizabeth Puscheck, Daniel Rappolee.
      Stress responses are essential for cellular survival and organismal, developmental progression. In somatic cells and embryonic stem cells (ESC), there exists the sequential transcriptional programs of the integrated stress response (ISR) and senescence-associated secretory phenotype (SASP), which enable stepwise adaptation to adverse conditions. We recently identified a distinct developmentally associated stress response (DASR) in mouse ESC that hypothetically emerges only after successful completion of cellular adaptation (ISR), reflecting a shift toward organismal-level adaptation. In explanation, a cellular response is a cell autonomous cell survival response, and it enables a stem cell response leading to organismal development and survival. Here, we test whether placental trophoblast stem cells (TSC), also undergo this ISR-DASR transition. Using transcriptomic profiling of mouse TSC exposed to strong, hyperosmotic stress (at 400mM sorbitol), we find that early responses (0.5-2 h) are dominated by biosynthetic and metabolic gene functions characteristic of cellular adaptation, whereas later responses (6-24 h) are enriched for developmental and differentiation pathways, consistent with DASR activation. These findings suggest that the ISR-DASR transition is a general feature of the response of stressed, developmental stem cells. They also highlight potential biomarkers for improving in vitro fertilization, understanding miscarriage, and advancing regenerative medicine.
    Keywords:  Cellular stress response; Developmentally associated stress response (DASR); Embryonic stem cells (ESC); Integrated stress response (ISR); Organismal homeostasis; Pluripotency; Transcriptomics; Trophoblast giant cells (TGC); Trophoblast stem cells (TSC)
    DOI:  https://doi.org/10.1038/s41598-026-55295-1
  18. PLoS Genet. 2026 Jun;22(6): e1012164
    RNA Polymerase III subunit Polr3a is required for craniofacial cartilage and bone development in zebrafish.
    Bailey T Lubash, Roxana Gutierrez, Nicole A Hansen, Kade Fink, Colette A Hopkins, Lauren B Sands, Jessica C Nelson, Kristin E N Watt.
      Transcription by RNA Polymerase III (Pol III) is essential for ribosome biogenesis and translation in all cells, but pathogenic variants in genes encoding subunits of Pol III lead to tissue-specific phenotypes including craniofacial differences. To understand the function of Pol III in craniofacial development, we examined polr3a mutant zebrafish. These mutants display hypoplasia of the neural crest cell-derived craniofacial cartilage and bone but, surprisingly, no significant changes were observed in neural crest cell proliferation or survival during embryogenesis. At larval stages, increased cell death was observed throughout the head, including in the craniofacial cartilage. These changes coincide with reduced transcription of transfer RNAs and reduced ribosome biogenesis in polr3a mutant zebrafish. To determine tissue-specific transcriptional changes, we performed single-cell RNA-sequencing. Analysis revealed both global and cartilage-specific changes, including upregulation of tp53. However, Tp53 inhibition alone was not sufficient to rescue craniofacial cartilage and bone, indicating that additional factors are important to support cartilage and bone growth in polr3a mutants. Altogether, our study provides new mechanistic insights into the functions of Pol III in craniofacial development.
    DOI:  https://doi.org/10.1371/journal.pgen.1012164
  19. Cell Rep. 2026 Jun 11. pii: S2211-1247(26)00623-6. [Epub ahead of print]45(6): 117545
    Nucleoplasmic checkpoint of the 40S ribosomal decoding center maturation.
    Benjamin Lau, Yi Li, Jingyi Zhu, Xianwen Ye, Paulina Fischer, Xiaying Hong, Rui Yuan, Roland Beckmann, Ed Hurt, Jingdong Cheng.
      The decoding center (DC) is a key ribosomal structure for accurate translation, assembled in a multi-step process that starts on nucleolar pre-ribosomes and ends in the cytoplasm. While late cytoplasmic steps and their checkpoint mechanisms are well characterized, the regulation of early nucleoplasmic DC assembly is unclear. Here, we show that the essential assembly factor Rrp12 plays a central coordinating role. Using Chaetomium thermophilum and cryo-electron microscopy analyses of fifteen pre-40S intermediates, we demonstrate that Rrp12 C terminus truncation: (1) inhibits release of the Utp14-Dhr1 pair, (2) displaces Tsr1, (3) promotes premature stabilization of h28, and (4) prevents h44 formation. These defects impair final 18S rRNA processing and prematurely activate the quality control kinase Rio1. Our results reveal a nucleoplasmic checkpoint during DC formation and establish Rrp12 as a critical regulator ensuring accurate assembly and orderly ribosome maturation.
    Keywords:  90S; CP: molecular biology; Chaetomium thermophilum; decoding center; helix28; helix44; pre-40S; premature RNA folding; quality control; ribosome assembly; rrp12
    DOI:  https://doi.org/10.1016/j.celrep.2026.117545
  20. Gastro Hep Adv. 2026 ;5(7): 100950
    Integrated Stress Response and Necroptosis Drive Epithelial Dysfunction in Crohn's Disease: Repurposing Cancer Drugs for Permeability Barrier Healing.
    Debasish Halder, Ritwika Biswas Lanford, Amin Esmaeilniakooshkghazi, Jason Ken Hou, Yaohong Wang, Seema Khurana.
       Background and Aims: Intestinal permeability dysfunction is a central pathogenic driver of Crohn's disease (CD), fueling microbial translocation, chronic inflammation, and progressive tissue injury. While current therapies suppress inflammation, none directly restore epithelial barrier function. Importantly, in patients with CD, epithelial barrier healing rather than mucosal healing is associated with long-term remission and a reduced risk of disease complications. Yet permeability barrier healing remains an unaddressed therapeutic target in CD. Here, we investigated whether pharmacologic inhibition of the integrated stress response (ISR) and RIPK3-mediated necroptosis, 2 convergent pathways of epithelial injury, can promote epithelial viability, regeneration, and barrier integrity in CD.
    Methods: We employed villin-1/gelsolin double knockout mice with epithelial-intrinsic ISR activation, Tnf ΔARE/+ mice with chronic inflammation, and CD patient-derived enteroids (PDEs). Animals and PDE were treated with integrated stress response inhibitor, RIPK3 inhibitor necrostatin-1, or US Food and Drug Administration-approved cancer drugs pazopanib and ponatinib, repurposed as potent RIPK3 inhibitors. Epithelial survival, regenerative growth (enteroid formation, budding), and barrier function (transepithelial electrical resistance) were assessed.
    Results: Chronic ISR activation and necroptosis were prominent in both murine models and CD PDEs, causing epithelial death, Paneth cell expansion, impaired enteroid survival, and regenerative failure. Pharmacologic inhibition with integrated stress response inhibitor, necrostatin-1, pazopanib, or ponatinib restored villus architecture, reduced inflammation, enhanced epithelial survival and regeneration, and significantly improved transepithelial electrical resistance.
    Conclusion: ISR activation and RIPK3-mediated necroptosis converge to drive epithelial injury and barrier dysfunction in CD. Repurposing pazopanib and ponatinib offers a potentially translatable approach to restore barrier integrity in CD.
    Keywords:  Crohn’s Disease; Integrated Stress Response; Necroptosis; Permeability Barrier Healing; RIPK3 Inhibitors
    DOI:  https://doi.org/10.1016/j.gastha.2026.100950
  21. RNA Biol. 2026 Dec;23(1): 1-14
    FTO-mediated m6A demethylation of BCL6 promotes gastric cancer progression by suppressing ferroptosis.
    Yan Wang, Fangfang Fan, Zhongmin Zhan, Chenxu Yu, Shengchi Chen.
      B-cell lymphoma 6 (BCL6) functions in various cancers, but its role and regulation in gastric cancer (GC) remain unclear. N6-methyladenosine (m6A) modification is critical for tumorigenesis, and the demethylase FTO (highly expressed in GC) may regulate target gene stability via m6A. This study explored FTO's regulation of BCL6 m6A modification and its impact on GC progression through ferroptosis. qPCR assessed BCL6 expression in GC cells. BCL6 overexpression models were used to evaluate cell viability, apoptosis, and ferroptosis (via ROS, Fe2+, MDA, LDH, and ferroptosis-related proteins). RIP-PCR, MeRIP-qPCR, and mRNA stability assays examined FTO-BCL6 mRNA interaction and m6A effects. YTHDF2 knockdown validated its role, and co-silencing FTO/BCL6 clarified the axis's function. BCL6 was downregulated in GC cells. Its overexpression inhibited cell viability, promoted apoptosis, and induced ferroptosis. FTO bound BCL6 mRNA, removed m6A, and reduced its stability. YTHDF2 mediated FTO's negative regulation of BCL6. FTO knockdown enhanced ferroptosis and impaired GC cell function, partially reversed by BCL6 silencing. FTO suppresses BCL6 via m6A demethylation, inhibiting ferroptosis to promote GC progression. The FTO/BCL6 axis is a potential therapeutic target for GC.
    Keywords:  BCL6; FTO; Gastric cancer (GC); N6-methyladenosine (m6A) modification; ferroptosis
    DOI:  https://doi.org/10.1080/15476286.2026.2684406
  22. mSphere. 2026 Jun 09. e0029726
    A long non-coding RNA, afu-254, is required for the oxidative stress response, cell wall stress response, azole susceptibility, and virulence in Aspergillus fumigatus.
    Ritu Devkota, Nava Raj Poudyal, Jazmin Reyes Servin, Julianna Lenz, Kelly M Shepardson, Sourabh Dhingra.
      Long non-coding RNAs play an important role in stress response in all forms of life; however, a tight regulation of lncRNAs is required for normal function. Abnormal expression of lncRNA is associated with uncontrolled cell growth in many forms of cancer. Recent studies have highlighted the role of lncRNAs in Aspergillus fumigatus in azole stress response and virulence. Here, using a transcriptome data set of A. fumigatus response to stress, we identified afu-254 as an 854 bp lncRNA that plays a role in modulating oxidative stress, fungal sub-MIC azole response to posaconazole and itraconazole, cell wall stress, macrophage phagocytosis and killing ex vivo, and virulence in an invertebrate model of Aspergillus infection. Importantly, afu-254 does not produce cross-azole susceptible responses and plays a role in fungal azole responses against posaconazole and itraconazole but not voriconazole. Furthermore, we showed that stoichiometric levels of afu-254 are important for its function, and ectopic overexpression of afu-254 in the WT strain leads to an antimorph. This phenotype may stem from a higher-order structure that is denatured with heat, indicating the presence of a non-functional isoform. In conclusion, we characterized a novel lncRNA, afu-254, that is important for stress response and virulence in the pathogenic fungus A. fumigatus.IMPORTANCEFailure of azole treatment for invasive Aspergillus infection by both drug-resistant and drug-sensitive isolates is an area of concern and global importance. Fungal stress response is multifaceted, and long non-coding RNAs have emerged as important players in mediating it, including regulating responses to azole antifungals. Here, we have identified a long non-coding RNA, afu-254, that plays a role in modulating fungal response to oxidative stress, cell wall stress, azole stress, immune cell stress, and virulence in an invertebrate model of invasive Aspergillus infection.
    Keywords:  antimorph; azole response; lncRNA; virulence
    DOI:  https://doi.org/10.1128/msphere.00297-26
  23. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2528970123
    Structural basis of long-range transcription-translation coupling.
    Chengyuan Wang, Vadim Molodtsov, Shashank Shandilya, Linlin You, Jing Zhang, Konstantin Kuznedelov, Bryce E Nickels, Jason T Kaelber, Gregor Blaha, Richard H Ebright.
      Structures recently have been reported of molecular assemblies that mediate transcription-translation coupling in Escherichia coli. In these molecular assemblies, termed "coupled transcription-translation complexes" or "TTC-B," RNA polymerase (RNAP) directly interacts with the ribosome, the transcription elongation factor NusG or its paralog RfaH forms a bridge between RNAP and ribosome, and the transcription elongation factor NusA optionally forms a second bridge between RNAP and ribosome. Here, we report structures of coupled transcription-translation complexes having mRNA spacers between RNAP and ribosome longer than the maximum-length mRNA spacer compatible with formation of TTC-B. The results define a class of coupled transcription-translation complex, termed "TTC-LC," where "LC" denotes "long-range coupling." TTC-LC differs from TTC-B by a ~60° rotation and ~70 Å translation of RNAP relative to ribosome, resulting in loss of direct interactions between RNAP and ribosome and creation of a ~70 Å gap between RNAP and ribosome. TTC-LC accommodates long mRNA spacers by looping out mRNA from the gap between RNAP and ribosome. We present evidence that TTC-LC is a functional intermediate in assembling and disassembling TTC-B, mediating pre-TTC-B transcription-translation coupling before a ribosome catches up to RNAP, and mediating post-TTC-B transcription-translation coupling after a ribosome stops moving and RNAP continues moving. We show that TTC-B, but not TTC-LC, is severely defective in RNA-hairpin-dependent transcription termination, and that both TTC-B and TTC-LC are severely defective in Rho-dependent transcription termination.
    Keywords:  NusG; RNA polymerase; RfaH; ribosome; transcription–translation coupling
    DOI:  https://doi.org/10.1073/pnas.2528970123
  24. Cells. 2026 Jun 05. pii: 1041. [Epub ahead of print]15(11):
    Ribosome Biogenesis as a Putative Bottleneck to Skeletal Muscle Hypertrophy: Mechanisms, Human Evidence, and Practical Modulators.
    Mario Muñoz López, José Francisco López-Gil, Xabier Ramírez de la Piscina Viúdez, Eneko Baz-Valle, José Francisco Tornero Aguilera.
       BACKGROUND: Skeletal muscle hypertrophy has traditionally been attributed to transient spikes in translational efficiency governed by the mTORC1 signaling cascade. However, contemporary molecular evidence reveals that sustained macroscopic growth is strongly associated with the physical expansion of the translational machinery itself. The activation of RNA Polymerase I and the subsequent synthesis of new ribosomes represent a critical biological correlate for long-term protein accretion.
    OBJECTIVE: This comprehensive review critically examines ribosome biogenesis as the primary structural bottleneck shaping human skeletal muscle adaptation, differentiating acute signaling efficiency from chronic translational capacity.
    SYNTHESIS: We dissect the molecular orchestration of nucleolar expansion and critically address the pervasive methodological pitfalls plaguing the current literature. Specifically, we highlight the moving denominator paradox, demonstrating how flawed bulk RNA normalization strategies systematically underestimate true ribosomal accretion in actively growing tissue. By synthesizing in vivo human evidence, we delineate how age, concurrent training, and training volume modulate this structural capacity. We further establish the high-responder phenotype as a function of successful nucleolar adaptation. Finally, we explore advanced molecular frontiers, including epigenetic chromatin remodeling, ribosomal heterogeneity as an emerging frontier, non-coding RNA regulation, and nuclear mechanotransduction via the YAP/TAZ axis.
    CONCLUSIONS: Acute anabolic signaling is merely permissive. Permanent hypertrophic adaptation fundamentally relies on overcoming the translational capacity bottleneck. Shifting the scientific and applied focus toward the architectural expansion of the nucleolus will fundamentally redefine practical hypertrophy programming and clinical interventions for sarcopenia.
    Keywords:  RNA Polymerase I; mechanotransduction; nucleolus; resistance training; ribosome biogenesis; skeletal muscle hypertrophy; translational capacity
    DOI:  https://doi.org/10.3390/cells15111041
  25. iScience. 2026 Jun 19. 29(6): 116170
    Conserved RNA helicase Vasa regulates ribonucleoprotein condensate dynamics and mRNA localization.
    Siran Tian, Hyosik Kim, Harrison A Curnutte, Tatjana Trcek.
      Germ granules are germline ribonucleoprotein condensates that concentrate proteins and mRNAs essential for animal development. Although the DEAD-box RNA helicase Vasa is a conserved core germ granule component, its role within these condensates remains poorly understood. Using Drosophila and human cell systems, we showed that condensation of Oskar (Osk), the fly germ granule nucleator, occurred independently of Vasa. However, in late oocytes lacking Vasa, Osk-eGFP formed aggregates and exhibited markedly reduced exchange with the aggregate surroundings. Consistently, Vasa increased Osk-eGFP condensate recovery in cells. Additionally, mRNA localization to germ granules was not persistent in oocytes lacking Vasa, while in cells, co-expression of Vasa and Osk was necessary and sufficient for mRNA localization to condensates. Notably, localization of nanos messenger ribonucleoprotein (mRNP) to condensates reduced Vasa-dependent enhancement of Osk-eGFP exchange. Together, our study reveals the DEAD-box RNA helicase Vasa as a central regulator of condensate dynamics and mRNP localization in vivo and in cellulo.
    Keywords:  cell biology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.116170
  26. Nat Commun. 2026 Jun 12.
    Ribosomal allostery as a potential regulator of bacterial dormancy.
    Danis Yangaliev, Eun Chae Moon, Gürol M Süel, S Banu Ozkan.
      Ribosomes are central to protein synthesis but also serve as dynamic hubs that integrate cellular stress responses. Here, we investigate how ribosomal protein L11 regulates ribosome conformational dynamics and long-distance coupling. Long-timescale molecular dynamics simulations of wild-type and L11-deleted (ΔL11) ribosomes reveal that L11 functions as a global allosteric regulator coordinating communication between the ribosomal stalk and the peptidyl transferase center. The absence of L11 disrupts long-distance couplings involving RelA and Obg and rigidifies the hibernation-promoting factor site, suggesting altered hibernation dynamics that could affect ribosome persistence under stress. To examine the physiological implications of these computational predictions, we construct a ΔL11 Bacillus subtilis strain and quantify its sporulation behavior. The ΔL11 variant exhibits delayed entry into and exit from dormancy, consistent with a breakdown in stress-adaptive ribosomal regulation. Overall, these results highlight the role of L11 in ribosomal allostery, suggesting how local perturbations propagate through the ribosome to influence global physiological outcomes and bacterial survival under environmental stress.
    DOI:  https://doi.org/10.1038/s41467-026-74199-2
  27. Signal Transduct Target Ther. 2026 Jun 09. pii: 224. [Epub ahead of print]11(1):
    Emerging perspectives in proteostasis: bridging mechanisms and therapeutics for human diseases.
    Ankush Borlepawar, Marco Neu, Ziqi Ma, Anushka Deshpande, Hannah Bühringer, Parvana Hajieva, Norbert Frey, Ashraf Yusuf Rangrez.
      Cellular protein homeostasis, or proteostasis, underpins the integrity, adaptability, and survival of all cells by balancing protein synthesis, folding, trafficking, and degradation. This multilayered network is sustained by coordinated actions of molecular chaperones, the ubiquitin‒proteasome system, autophagy-lysosomal pathways, and organelle-specific quality control programs. When this equilibrium collapses, misfolded, aggregated, or damaged proteins accumulate, driving organelle dysfunction, maladaptive stress signaling, and disease progression. Disruption of proteostasis is now recognized as a unifying pathological hallmark linking neurodegenerative disorders, cancer, cardiovascular and metabolic diseases, and autoimmune conditions. This is particularly consequential in post-mitotic organs such as the heart and brain, which possess limited regenerative capacity and are exceptionally vulnerable to proteotoxic stress. Rapid advances now reveal proteostasis as a multicomponent, cross-compartmental, and dynamically adaptable system, rather than isolated pathways. We frame this complexity through the concept of proteostasis resilience, defined as the ability of cells and tissues to maintain proteome stability under stress, and use it to unify disease mechanisms with therapeutic opportunity. This review integrates mechanistic insights with translational advances, outlining how dysregulation of chaperones, autophagy-mitophagy, the ubiquitin‒proteasome system, and ER stress pathways drive human diseases, while highlighting emerging therapeutic platforms, from pharmacological chaperones and autophagy modulators to targeted protein degradation technologies, CRISPR screens, spatial biology, and AI-guided drug discovery. Together, this systems-level perspective positions proteostasis resilience as a foundational paradigm for understanding disease vulnerability and designing precision proteostasis-based therapies.
    DOI:  https://doi.org/10.1038/s41392-026-02714-4
  28. J Exp Bot. 2026 Jun 11. pii: erag288. [Epub ahead of print]
    Biomolecular Condensates in Plant Stress and Development: Recent Advances and Emerging Concepts.
    Israel Maruri-Lopez, Itzell E Hernandez-Sanchez, Malavika Muraleedharan, Monika Chodasiewicz.
      Biomolecular condensates have emerged as a central paradigm for understanding how plant cells organize biochemical processes without membrane boundaries, particularly under fluctuating environmental conditions. In plants, many condensates are thought to form through liquid-liquid phase separation and related demixing behaviors, enabling the selective concentration of proteins and RNAs into dynamic assemblies. This mesoscale organization provides an efficient strategy to buffer acute stress, protect macromolecules, and reprogram gene expression across spatial and temporal scales. Here, we synthesize current knowledge of condensate functions in plant development and stress responses, with a focus on Arabidopsis thaliana, where mechanistic insights are most advanced. We first outline the biophysical principles underlying condensate formation, emphasizing multivalent protein-protein and protein-RNA interactions, intrinsically disordered regions, and prion-like or low-complexity domains that enable reversible assemblies with distinct material properties. We then discuss condensates in plant development, highlighting hydration-associated assemblies in seeds, as well as condensation-based regulation of light signaling, auxin pathways, and flowering time. Next, we examine condensates as key hubs of stress adaptation, including stress granules and processing bodies, nuclear assemblies, and emerging evidence for organellar condensates in chloroplasts, which may exhibit distinct biophysical characteristics. Finally, we review the experimental toolkits used to study condensates in plants, ranging from live-cell imaging and fluorescence recovery after photobleaching (FRAP) to in vitro reconstitution, proximity labeling, particle enrichment strategies, and RNA-centric profiling approaches, while emphasizing important technical considerations and limitations. We conclude by outlining key open questions such how plants dynamically regulate condensate assembly and disassembly in vivo, how condensates interface with proteostasis and organelle function, and how this layer of regulation may contribute to plant resilience in the context of climate change.
    Keywords:  Arabidopsis; Biomolecular condensates; LLPS; RNA-binding proteins; abiotic stress; plant development; stress granules
    DOI:  https://doi.org/10.1093/jxb/erag288
  29. PLoS Genet. 2026 Jun 09. 22(6): e1012162
    The importance of nonsense errors: Estimating the rates and implications of ribosome drop-off during protein synthesis.
    Alexander L Cope, Denizhan Pak, Michael A Gilchrist.
      The process of translation is both energetically costly and relatively error-prone compared to transcription and replication. Nonsense errors during translation occur when a ribosome drops off a transcript before reaching a stop codon, resulting in energetic investment in an incomplete and likely non-functional protein. Nonsense errors impose a potentially significant energy burden on the cell, making it critical to quantify their frequency and energetic cost. Here, we present a model of ribosome movement for estimating protein production, elongation, and nonsense error rates from high-throughput ribosome profiling data. Applying this model to an exemplary ribosome profiling dataset in S. cerevisiae, we find that nonsense error rates vary substantially between codons and that these types of errors place an energetic burden on cells comparable to ribosome pausing. Overall, we present multiple lines of evidence that selection against nonsense errors is a prominent force shaping protein-coding sequence evolution and codon usage bias, in particular.
    DOI:  https://doi.org/10.1371/journal.pgen.1012162
  30. PLoS Pathog. 2026 Jun 11. 22(6): e1013722
    The assembly of stress granules during foot-and-mouth disease virus infection is uncoupled from activation of cellular intrinsic antiviral signalling.
    Mariana Marques, Yui Xi Wong, Zhaozhi Sun, Amina Yasmin, J Paul Taylor, Alessia Ruggieri, Tobias J Tuthill, Nicolas Locker.
      Foot-and-mouth disease virus (FMDV) is highly contagious among cloven-hoofed animals and poses a major threat to the livestock industry worldwide. A fundamental gap in knowledge for high consequence viruses such as FMDV is understanding how the virus evolved to evade cellular antiviral responses. FMDV belongs to the Picornaviridae, a family of positive-sense single-stranded RNA viruses. The detection of viral double-stranded viral RNA intermediates during infection can trigger both the assembly of cytoplasmic stress granules (SGs) and the activation of the RIG-I-like receptors (RLR)-mediated innate immune response (IIR). FMDV has been proposed to antagonize these mechanisms, suggesting that both can limit viral replication. In this study, we investigate the dynamic and importance of SG assembly for IIR activation upon dsRNA stimulation or FMDV replication in porcine epithelial kidney cells. First, we show that the formation of SG following a challenge with poly(I:C), a viral dsRNA mimic, does not modulate the activation of IIR. Our data further reveal transient assembly of SG during FMDV infection followed by virus-induced cleavage of G3BP1, a core SG protein. While SG assembly does not impact viral replication or antiviral response activation, we demonstrate that preventing their disassembly negatively impacts FMDV replication. Overall, we show that SGs assembly during infection does not modulate viral replication and is uncoupled from IIR activation, while FMDV actively cleaves G3BP1 by a 3Cpro-mediated mechanism to promote their disassembly, suggesting a potential antiviral role for persistent SGs.
    DOI:  https://doi.org/10.1371/journal.ppat.1013722
  31. Nat Commun. 2026 Jun 09. pii: 4963. [Epub ahead of print]17(1):
    Structural insights into YheS-mediated release of SecM-arrested ribosome.
    Kaishi Iso, Toma Ikeda, Kohei Yamasaki, Yushin Ando, Fumiya K Sano, Tadaomi Furuta, Hideki Taguchi, Osamu Nureki, Yuhei Chadani, Yuzuru Itoh.
      ATP-binding cassette subfamily F (ABCF) proteins interact with the ribosome to resolve translation defects near the peptidyl transferase center (PTC). In Escherichia coli, four ABCF proteins (EttA, Uup, YbiT, and YheS) selectively promote translation of distinct problematic nascent peptide sequences, but their molecular mechanisms remain unclear. Here, we present a 2.8 Å cryo-EM structure of the ribosome in complex with an ATPase-deficient mutant of YheS and investigate how it releases ribosomes arrested by the SecM nascent chain. YheS binds to the ribosomal E-site via the L1 stalk, and its P-site tRNA-interaction motif (PtIM) extends toward the PTC, displacing the CCA end of the P-site tRNA. Notably, the cryo-EM density corresponding to the SecM nascent chain within the exit tunnel is largely lost upon YheS binding. These observations suggest that YheS relieves peptide sequence-dependent stalling by perturbing nascent chain-tunnel interactions through P-site tRNA relocation. Steered molecular dynamics simulations provide qualitative support for this model. Together, our findings provide mechanistic insight into a mode of arrest release distinct from the translocon-mediated release mechanism.
    DOI:  https://doi.org/10.1038/s41467-026-72863-1
  32. Nat Commun. 2026 Jun 11.
    TRNAU1AP and PRPF39 establish integrated control over processing of most abundant human non-coding RNAs.
    Monireh Panah, Rui Che, Bhoomi Mirani, Xiaotong Chen, Hong Luo, Andrei Alexandrov.
      Although abundance of the metastasis-associated long non-coding RNA MALAT1 depends on the maturation of its triple-helix-containing 3' end via non-canonical processing, the control of this step has remained unknown. Using iterative genome-wide screening, we identified TRNAU1AP and PRPF39 that together control the 3'-end processing of MALAT1, enabling a reduction in its levels. We further show that these factors form part of a previously unrecognized RNase MRP and P control (RMPPc) pathway that, in addition to MALAT1, establishes integrated control over the processing of MEN-β, internal transcribed spacers in pre-rRNA, and 5'-leader sequences in pre-tRNA, thereby impacting fundamental processes prerequisite for translation. We demonstrate that this far-reaching impact is achieved through a single control point: inclusion of the initiating ATG-containing exon 2 in RPP14, an essential component of both RNase MRP and RNase P, thereby controlling both catalytic RNAs-MRP RNA and H1 RNA. Finally, we show that upstream of this primary control point, the RMPPc pathway forms a remarkably interlinked four-pronged feedback circuit that confers stability on post-transcriptional processing of over 90% of the total RNA content in human cells.
    DOI:  https://doi.org/10.1038/s41467-026-74036-6
  33. Nucleic Acids Res. 2026 Jun 08. pii: gkag555. [Epub ahead of print]54(11):
    AMPK tunes reproductive gene expression and small RNA homeostasis to mediate timely germ cell development.
    Sabih Rashid, Fabian Braukmann, Eric A Miska, Richard Roy.
      Developmental plasticity allows organisms to adapt to environmental stressors and improve fitness. Caenorhabditis elegans can enter an alternative larval stage, the dauer, marked by developmental quiescence and complete transcriptomic remodeling. The energy modulator AMPK is required for animals to passage through dauer while preserving germline quiescence. Without AMPK, dauer animals exhibit reproductive defects, which are partially suppressed by disabling small RNA pathway components. To understand how the loss of AMPK affects RNA homeostasis and gene expression, we performed transcriptomic analysis of AMPK mutants. We reveal that over 60% of the C. elegans genes are affected by the loss of AMPK during the dauer stage. This is accompanied by a widespread increase in reproductive gene expression in dauer, as well as the upregulation of most small RNAs and small RNA pathway components, particularly the spermatogenic Argonautes ALG-3/4. Eliminating ALG-3/4 corrects several reproductive defects, including premature dauer spermatogenesis, and partially restores fertility. Notably, decreasing global small RNA biogenesis also partially corrects these phenotypes, possibly by destabilizing their associated Argonaute effectors. Our work highlights a role for AMPK in the temporal regulation of small RNA populations to establish a delicate balance that is essential for reproductive fitness following quiescence during periods of stress.
    DOI:  https://doi.org/10.1093/nar/gkag555
  34. Cell Rep. 2026 Jun 08. pii: S2211-1247(26)00404-3. [Epub ahead of print]45(6): 117326
    Human J-domain proteins promote stress granule disassembly and suppress neurodegeneration-linked protein aggregation.
    Giovanni J Mastromarco, Rebecca Earnshaw, Gaelen Moore, X Y Sherwin Xu, Nour H Sadek, Fiona Cui, Natalie Lo, Hyun O Lee.
      Stress granules are conserved biomolecular condensates that form under stress and rapidly disassemble during recovery. Stress granules have been linked to pathological protein aggregation and their impaired disassembly reduces cell viability, yet the mechanisms governing their clearance and protein aggregation remain unclear. We find that human HSP70 and a subset of J-domain proteins (JDPs) localize to stress granules and that chemical or genetic inhibition of these chaperones markedly slows granule disassembly. Conversely, overexpressing these JDPs, particularly DNAJB1, accelerates disassembly without altering assembly. In vitro, HSP70 and DNAJB1 partition into G3BP1 condensates and reduce their size in an ATP-dependent manner. In cells expressing amyotrophic lateral sclerosis (ALS)-linked mutant FUS, DNAJB1 depletion further impairs stress granule clearance and promotes pre-amyloid accumulation, while depleting a non-stress granule JDP has no effect. Our findings demonstrate that specific JDP chaperones enhance stress granule disassembly and help limit aberrant protein aggregation.
    Keywords:  ALS; CP: molecular biology; CP: neuroscience; FUS; HSP70; J-domain proteins/HSP40; biomolecular condensates; cellular stress response; molecular chaperones; neurodegeneration; protein aggregation; stress granules
    DOI:  https://doi.org/10.1016/j.celrep.2026.117326
  35. Biochem Biophys Res Commun. 2026 Jun 05. pii: S0006-291X(26)00875-2. [Epub ahead of print]828 154111
    Altered translation efficiency of specific mRNAs in a zebrafish model of Diamond-Blackfan anemia syndrome.
    Tamayo Uechi, Mariko Nagatomo, Yukari Nakajima, Yutaka Suzuki, Naoya Kenmochi.
      Diamond-Blackfan anemia syndrome (DBAS) is a congenital pure red-cell aplasia that is often accompanied by physical deformities. Heterozygous mutations in more than 20 ribosomal protein (RP) genes have been linked to the disease. The most frequently mutated gene is RPS19, which accounts for 25% of the patients. Haploinsufficiency of the RP genes may affect translation of specific mRNAs that could be related to the anemia. However, the underlying mechanisms are still unclear. To evaluate the impacts of RP depletion on translation, using a zebrafish model of DBAS with knockdown of the RPS19 ortholog (rps19), we compared changes in polysomal mRNAs with those in total mRNAs in the DBAS model to examine the translation efficiency of individual transcripts. As a result, we calculated the translation efficiency of 5464 transcripts. Among them, the transcripts from 75 genes exhibited translational repression to less than half compared to the controls. Erythropoiesis-related genes were enriched among the repressed genes. Unexpectedly, some genes related to glycan biosynthesis were also translationally repressed. One of these was the pigq gene, which participates in a glycosylphosphatidylinositol-anchor biosynthesis. We injected synthesized pigq mRNA into embryos with rps19 knockdown (the DBAS model), and found that the anemia phenotype was rescued, but morphological defects were not, indicating its role in erythropoiesis in zebrafish. These results suggest that impaired translation of erythropoiesis-related and glycan biosynthesis-related genes is implicated in the pathogenesis of DBAS.
    Keywords:  Diamond-Blackfan anemia syndrome; Polysome profiling; Ribosomopathy; Translation efficiency; Zebrafish model
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154111
  36. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2602470123
    High-throughput screening identifies a critical role of the SPOP-PABPC1 axis in lung adenocarcinoma progression.
    Jiahui Zhang, Ran Liu, Xue Han, Yutong Jiao, Yun Peng, Zizhang Zhou, Yanran Deng, Lianggeng Gong.
      Lung adenocarcinoma (LUAD) is the most common and deadly subtype of lung cancer, with limited therapeutic options and poor prognosis. Ubiquitination is an important posttranslational modification (PTM) that controls protein turnover, localization and interaction. The dysregulated ubiquitination machinery is a hallmark of cancer, contributing to tumor development. Identifying key E3 ubiquitin ligases and deubiquitinases in LUAD could lead to new biomarkers and treatments. Through RNA sequencing, bioinformatics, and clinical studies, SPOP has been identified as a promising E3 ligase target in LUAD. SPOP is downregulated in LUAD samples and associated with poorer patient outcomes. Functional analyses demonstrate that SPOP suppresses LUAD cell migration, proliferation, and in vivo tumor growth. Mechanistically, SPOP targets poly(A)-binding protein cytoplasmic 1 (PABPC1) for nonproteolytic ubiquitination, leading to its nuclear retention and inhibition of global protein synthesis, thereby suppressing the oncogenic effects of PABPC1. Furthermore, the deubiquitinase HAUSP is able to counteract SPOP-mediated ubiquitination of PABPC1, enhancing its oncogenic role in LUAD cells. Collectively, our findings reveal a SPOP/HAUSP-PABPC1 regulatory axis in LUAD, where SPOP and HAUSP oppositely modulate PABPC1 ubiquitination to control LUAD cell proliferation and migration. This axis represents a promising therapeutic target in LUAD.
    Keywords:  HAUSP; LUAD; PABPC1; SPOP; nondegradative ubiquitination
    DOI:  https://doi.org/10.1073/pnas.2602470123
  37. CNS Neurol Disord Drug Targets. 2026 Jun 08.
    Understanding the OMA1-DELE1-HRI Axis and PINK1-parkin-mediated Mitophagy in Parkinson's Disease.
    Shalini Singh, Anisha Sharma, Ravi Kumar Rajan, Manodeep Chakraborty, Ananya Bhattacharjee.
       INTRODUCTION: Mitochondrial dysfunction plays a crucial role in the pathogenesis of Parkinson's disease (PD). PINK1-Parkin-mediated mitophagy is a quality-control system for mitochondria that protects neurons by getting rid of damaged mitochondria. The OMA1-DELE1-HRI axis has recently been recognized as a vital regulatory checkpoint that limits excessive mitophagy and prevents metabolic failure during mitochondrial stress. The aim of this review is to analyze the mechanistic interplay between the PINK1-Parkin pathway and the OMA1-DELE1-HRI signaling axis. This study aims to synthesize current research on the influence of the stress-response pathway on the initiation of mitophagy, maintenance of mitochondrial homeostasis, and neuronal survival in PD.
    METHODS: A comprehensive literature review was conducted of molecular, genetic, and pharmacological studies on OMA1, DELE1, and HRI. A thorough analysis of data from kinome-wide screening assays, genetic knockdown experiments, multi-omics profiling, and structural biology studies was performed to elucidate the regulatory interactions between HRI and PINK1 under mitochondrial stress conditions.
    RESULT: The OMA1-DELE1-HRI pathway stops PINK1 from being stable by controlling how mitochondria make proteins and how they respond to stress. This inhibition serves as a metabolic safeguard that regulates mitophagy levels, preventing harmful overactivation. HRI seems to change PINK1-dependent mitophagy while having little effect on other pathways that clear things at the same time. This suggests that HRI has different substrate preferences and signaling specificity.
    DISCUSSION: The OMA1-DELE1-HRI axis is an important negative regulator of mitophagy that PINK1 and Parkin mediate. It stops too much mitochondrial clearance and metabolic failure in Parkinson's disease. This mechanism preserves bioenergetic homeostasis and promotes neuronal survival, suggesting that HRI is a promising therapeutic target. Inhibitors like ISRIB or heme mimetics may selectively restore mitophagy, thereby enhancing neuroprotection and enabling precision therapies guided by biomarkers such as phosphorylated eIF2.
    CONCLUSION: The OMA1-DELE1-HRI axis is a distinctive regulatory mechanism for mitochondrial quality control, significantly impacting neuroprotection in Parkinson's disease. Understanding its dual role in controlling mitophagy and maintaining bioenergetic homeostasis opens new possibilities for targeted drug development. Subsequent research should focus on structural and pharmacological modifications of HRI to enhance mitophagy while preventing mitochondrial depletion.
    Keywords:  DELE1; HRI (heme-regulated inhibitor kinase); ISR (integrated stress response); OMA1; PINK1; Parkin; Parkinson’s Disease (PD).; mitophagy
    DOI:  https://doi.org/10.2174/0118715273469080260515103009
  38. Cell. 2026 Jun 08. pii: S0092-8674(26)00576-3. [Epub ahead of print]
    mRNA 3' UTRs chaperone intrinsically disordered regions to control protein activity.
    Yang Luo, Yaofeng Zhong, Sudipto Basu, Ming-Chung Wu, Christine Mayr.
      More than 2,700 human mRNA 3' UTRs have hundreds of highly conserved nucleotides, but their biological roles are unclear. These mRNAs encode proteins strongly enriched for long intrinsically disordered regions (IDRs) with hydrophobic amino acid clusters. For MYC, UTX, and JMJD3, we show that their mRNA 3' UTRs control protein activity. Rather than affecting protein abundance or localization, we find that the KDM6B 3' UTR co-translationally changes the folding of JMJD3 protein. It promotes IDR-IDR interactions and suppresses folding between domains, suggesting that RNA has IDR chaperone activity that prevents interference between hydrophobic clusters in the IDR with folding of the structured domain. 3' UTRs with chaperone activity are multivalent and mesh-like condensate-enriched, indicating the presence of localized folding environments for IDR-containing proteins. We show here that the protein sequence is insufficient for the biogenesis of fully active IDR-containing transcriptional regulators in cells, suggesting that mRNA 3' UTRs control their activity by preventing co-translational misfolding.
    Keywords:  3′ UTR; RNA multivalency; RNA-based chaperone activity; RNA–IDR interaction; chromatin regulator; co-translational; crosslinking mass spectrometry; hydrophobic clusters; intrinsically disordered regions; mesh-like condensates; protein folding; transcription factor
    DOI:  https://doi.org/10.1016/j.cell.2026.05.017
  39. Front Immunol. 2026 ;17 1844225
    Enhancing targeted strategies for cancer immunotherapy by elucidating mRNA processing mechanisms.
    Xiao Lu, Wenwen Gan, Jiang Yuan, Zhihao Chen.
      Immune checkpoint inhibitors have transformed the landscape of cancer therapy; however, the challenge that most patients do not achieve durable benefits urgently necessitates the development of new strategies that extend beyond mere T-cell activation. mRNA processing-comprising alternative splicing, RNA modifications, and RNA editing-establishes a dynamically regulated connection between the intrinsic characteristics of tumors and anti-tumor immunity. This review systematically summarizes how mechanistic insights into these processes can be translated into concrete approaches that enhance the precision of immunotherapy. We first outline how the widely dysregulated splicing events in tumor cells produce abundant neoantigens at a frequency that significantly exceeds that of gene mutations. A subset of these splice isoforms is shared among patients, offering a unique antigen resource for the development of 'off-the-shelf' mRNA vaccines, thereby circumventing the manufacturing bottleneck associated with personalized vaccines. Concurrently, RNA modifications driven by N6-methyladenosine (m6A) create an immunosuppressive network at the epitranscriptomics level by bidirectionally modulating the stability of immune checkpoint molecules, e.g., Programmed Death-Ligand 1 (PD-L1), and the functional polarization of macrophages and dendritic cells. In parallel, Adenosine Deaminase Acting on RNA 1 (ADAR1)-mediated Adenosine-to-Inosine (A-to-I) editing designates endogenous double-stranded RNA as 'self,' allowing tumors to evade innate immune surveillance and conceal 'non-self' signals. This includes the exploitation of splicing-derived neoantigens for designing personalized or shared mRNA vaccines, the deployment of small-molecule inhibitors targeting FTO, Methyltransferase Like 3 (METTL3), and YTH Domain Family Member 2 (YTHDF2) to alleviate immunosuppression, and the utilization of antisense oligonucleotides to precisely modulate splicing factor activity, thereby reversing T-cell exhaustion. Building on this foundation, the combination of these strategies with immune checkpoint blockade has already demonstrated clear synergistic effects in preclinical models and early-phase trials. Additionally, biomarkers based on splicing signatures and expression levels of modification enzymes show promise for accurately stratifying benefiting populations. Despite challenges such as off-target toxicity, intratumoral heterogeneity, and delivery technologies, cutting-edge tools like single-cell and long-read sequencing are rapidly bridging the translational gap. Strategies targeting mRNA processing are advancing cancer immunotherapy from a model of "broad-spectrum activation" to a new paradigm of "precision modulation."
    Keywords:  RNA modification; alternative splicing; immunotherapy; mRNA processing; tumor immunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1844225
  40. J Mol Endocrinol. 2026 Jun 11. pii: JME-25-0159. [Epub ahead of print]
    Pancreatic β-Cell Aging in Physiology and Diabetes: Emerging Roles of m6A mRNA Methylation.
    Lenee Shrestha, Dario F De Jesus.
      Pancreatic β-cells are essential for glucose homeostasis and particularly vulnerable to age-related stress. Aging is a fundamental biological process characterized by the progressive functional decline of tissues and organs and defined by several connected hallmarks. In Type 1 and Type 2 diabetes, aging is accelerated-manifesting as DNA damage response, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction, collectively driving β-cell dysfunction and senescence. N6-methyladenosine (m6A) is the most prevalent internal messenger RNA (mRNA) modification in eukaryotes. Emerging evidence demonstrates that m6A levels change with age in a tissue-specific manner, contributing to cellular dysfunction and age-related disease. In pancreatic β-cells, m6A hypomethylation compromises identity, survival, and function through mechanisms that include the IGF1 and insulin signaling pathways. Understanding how m6A methylation is regulated in aged β-cells may uncover new therapeutic strategies aimed at preserving β-cell functional mass and promoting healthy aging. This review focuses on pancreatic β-cell aging in physiological and diabetic conditions and examines the emerging role of m6A methylation in aging and diabetes progression.
    DOI:  https://doi.org/10.1530/JME-25-0159
  41. Sci Rep. 2026 Jun 11.
    IGF2BP3 promotes epithelial ovarian cancer progression by regulating FASN expression.
    Danting Sun, Yuance Xu, Jiaze Gao, Lin Cheng, Yapei Su, Yan Xu, Junqi He, Teng Lv.
      Ovarian cancer (OC) is the most lethal disease among female reproductive system tumors, particularly epithelial ovarian cancer (EOC). N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic RNA and is involved in gene expression regulation. In OC, high expression of the m6A reader protein IGF2BP3 predicts a poor prognosis, but the target molecules and mechanisms underlying this association remain unclear. This study demonstrates that IGF2BP3 promotes EOC progression by recognizing and stabilizing m6A-modified FASN mRNA, thereby activating the WNT/β-catenin signaling pathway. This activation enhances lipid synthesis, increases mitochondrial membrane potential, shortens S-phase duration, and promotes cell proliferation and metastasis. Mechanistically, IGF2BP3 binds to m6A-modified FASN mRNA to enhance its stability, and pharmacological inhibition of FASN by orlistat reverses IGF2BP3-mediated oncogenic effects and WNT/β-catenin activation. In vivo and in vitro experiments confirm that knocking down either IGF2BP3 or FASN reverses these malignant phenotypes. These findings highlight a novel m6A-dependent IGF2BP3-FASN-WNT axis that drives EOC progression, providing a potential biomarker for targeted therapy.
    Keywords:  EOC; FASN; IGF2BP3; N6-methyladenosine
    DOI:  https://doi.org/10.1038/s41598-026-57059-3
  42. Front Genet. 2026 ;17 1846555
    A 3'UTR polymorphism disrupts IRF2BP2 autoregulation through an eIF4H translational enhancer.
    An Duong, Hsiao-Huei Chen, Alexandre F R Stewart.
       Introduction: Interferon regulatory factor 2 binding protein 2 (IRF2BP2) suppresses the interferon response and inflammation. Individuals who carry 2 copies of a genetic variant (rs3045215) that deletes 9 nucleotides from the long 3'UTR of IRF2BP2 have lower IRF2BP2 protein expression in white blood cells and increased risk of coronary atherosclerosis and calcification.
    Methods and Results: RNAfold revealed that the deletion variant of IRF2BP2 disrupts an RNA stem-loop structure that can recruit the eukaryotic initiation factor 4H (eIF4H) to facilitate translation. siRNA knockdown of eIF4H reduced expression of endogenous IRF2BP2 protein. Similarly, it impaired translation of a luciferase reporter bearing the whole 3'UTR of IRF2BP2 but had no effect on one bearing the 9-nucleotide deletion variant (rs3045215). This deletion variant happens to be co-inherited with an IRF2BP2 coding variant that changes proline to serine at position 78. Overexpression of either isoform of IRF2BP2 (Pro78 or Ser78) suppressed translation of the luciferase reporter containing the whole IRF2BP2 3'UTR to the same level but had no effect on the deletion-bearing reporter. RNA gel mobility shift assay using cytosolic extracts of LPS-stimulated THP1 macrophages revealed that the 9-nucleotide deletion variant prevents endogenous IRF2BP2 protein from interacting with its own 3'UTR RNA sequences.
    Conclusion: The rs3045215 9-nucleotide deletion that increases the risk of heart disease abolishes IRF2BP2 autoregulation through an eIF4H-dependent translational enhancer.
    Keywords:  eukaryotic translation initiation factor 4H; genetic polymorphism; interferon regulatory factor (IRF); macrophage; translation regulation
    DOI:  https://doi.org/10.3389/fgene.2026.1846555
  43. PNAS Nexus. 2026 Jun;5(6): pgag187
    A transfer RNA inosine modification drives genome-wide synonymous recoding across human commensal bacterial families.
    Christopher D Katanski, Chathuri Pathirage, Jennifer C Chang, Iva Veseli, Tyler J Smith, Marcus Foo, Yuan Wu, Yichen Hou, Hoang Anh V Tran, Dominika Rudzka, Wen Zhang, Mohammad Amin Bayat Tork, Karen Lolans, Amy D Willis, Weixin Tang, A Murat Eren, Michael J Federle, Kristin S Koutmou, Tao Pan.
      Inosine modification on transfer RNA (tRNA) anticodon (I34) is universally conserved in three kingdoms of life and critical to tRNA decoding capabilities. We found that tRNALeu(IAG) in commensal human bacterial families in Lactobaccilalles is concurrent with genome-wide synonymous leucine codon reprogramming. Pathway analysis reveals significant synonymous Leu codon changes in proteins in multiple KEGG pathways on cellular metabolism, where many genome-wide dominant UUA in families without tRNALeu(IAG) is reprogrammed to CUU, CUC, and UUG in families with tRNALeu(IAG). We provide biochemical and phenotypic results to support mechanisms that enable synonymous Leu codon substitutions to confer greater translation equivalency and growth fitness, indicating that a tRNA inosine modification can propel the genome-wide evolution of synonymous leucine codons.
    Keywords:  codon evolution; genomics; inosine; tRNA
    DOI:  https://doi.org/10.1093/pnasnexus/pgag187
  44. bioRxiv. 2026 Jun 07. pii: 2026.05.31.729126. [Epub ahead of print]
    Heme orchestrates a tissue stress response to proteolytic damage.
    Karen Agaronyan, Allison M Greaney, Shuang Yu, Arun R Chavan, Darine W El-Naccache, Edward P Manning, Lokesh Sharma, Charles S Dela Cruz, Ruslan Medzhitov.
      Whereas cellular stress responses are well defined, tissue-level stress remains poorly understood. Proteases are among the most widespread enzymes, and excessive proteolytic activity drives diseases such as arthritis and chronic obstructive pulmonary disease, yet unifying features of this stress are unclear. Here, using the lung and diverse proteases, we identify a conserved injury signature of proteolytic stress marked by vascular disruption, red blood cell extravasation, and heme release that triggers oxidative stress. We show that alveolar macrophages act as primary sensors of this stress response, activating NRF2-dependent heme detoxification program and fibroblasts produce protease inhibitors to limit damage. Repeated exposure to proteolytic stress induces tissue adaptation and protects against subsequent injury and infection. These findings define a unifying framework for tissue-level proteolytic stress sensing and adaptation.
    DOI:  https://doi.org/10.64898/2026.05.31.729126
  45. Hemasphere. 2026 Jun;10(6): e70377
    A RiboCancer cell line panel reveals that CLL-associated Rps15 mutations translationally rewire transcription through codon-specific tRNA accommodation defects.
    Anaïs Astier, Marino Caruso, Stijn Vereecke, Paulo E Santo, Coralie Capron, Carine Froment, Dana Rinaldi, David Cabrerizo Granados, Marine Leclercq, Jonathan Royaert, Jelle Verbeeck, Naomy Pasau, Laura Plassart, Daniele Pepe, Steven Verbruggen, Hermes Paraqindes, Simon Lebaron, Virginie Marcel, Sébastien Durand, Clément Chapat, Gerben Menschaert, Pierre Close, Francesca Rapino, Frédéric Catez, Julien Marcoux, Célia Plisson-Chastang, Kim De Keersmaecker.
      Recurrent point mutations in ribosomal proteins (RPs) RPL10 and RPS15 are found in T-cell acute lymphoblastic leukemia (T-ALL) and chronic lymphocytic leukemia (CLL), respectively. Furthermore, deletions of RPL5, RPL11, and RPL22 are frequent in hematologic diseases such as Diamond Blackfan Anemia, T-ALL, multiple myeloma, and in a variety of solid tumors. Yet, the role of these RP defects in dysregulation of the ribosomal translation function remains poorly understood. We engineered an isogenic RiboCancer cell line library modeling the most recurrent RP defects in blood and solid cancers and characterized it by a multi-omics translatome analysis (proteome, Ribo-seq, and total RNA-seq) as well as RiboMethSeq. Within this RiboCancer panel, CLL-associated Rps15 mutations induced the strongest alterations in mRNA translation, affecting up to 10% of expressed genes. Cryo-electron microscopy revealed that these mutations destabilize the Rps15 C-terminus and affect the translation elongation cycle dynamics by deregulating accommodation of aminoacylated tRNAs at the ribosomal A-site. This accommodation defect showed specificity for 11 codons, explaining the reduced translation efficiency of genes with high presence of these codons in Rps15-mutant cells. Notably, these genes were enriched for epigenetic and transcriptional regulators such as transcription factor Runx3, resulting in downregulation of Runx3 target genes involved in immune regulation. By developing and characterizing a unique RiboCancer cell line panel, we mapped translational rewiring driven by the most frequent somatic RP mutations. We provide unprecedented mechanistic insights into translation defects induced by CLL-associated Rps15 mutations, and reveal an intriguing translation-based rewiring of transcription in CLL.
    DOI:  https://doi.org/10.1002/hem3.70377
  46. J Cardiothorac Surg. 2026 Jun 12.
    m6A-modified ATF4 regulates glucose/lipid metabolism via the Sestrin2/GSK3β axis to alleviate myocardial ischemia-reperfusion injury.
    Jie Wu, Jian Tong, Fen Zhang, Xingxing Li, Xizhi Liu, Yang Dong.
       BACKGROUND: Myocardial ischemia-reperfusion injury (MIRI) is a critical complication in the treatment of cardiovascular diseases, and its pathogenesis is closely associated with mitochondrial dysfunction and the imbalance of glucose/lipid metabolism. This study aims to investigate the molecular mechanisms underlying glucose/lipid metabolism in MIRI and identify potential therapeutic targets.
    METHODS: Key genes and prognostic biomarkers related to MIRI were identified through bioinformatics analysis, and a hypoxia/reoxygenation (H/R) model using HL-1 cardiomyocytes was employed to simulate the pathological process of MIRI. RNA interference was used to knock down ATF4, and bioinformatics analysis identified key molecules involved in m6A methylation. The regulatory mechanism of ATF4 mRNA stability mediated by RBM15 was further explored. Flow cytometry, mitochondrial membrane potential, and ATP assays were conducted to evaluate cell apoptosis, glucose uptake, fatty acid oxidation, and mitochondrial function.
    RESULTS: Bioinformatics analysis and the H/R model experiments in HL-1 cardiomyocytes revealed that ATF4 was highly expressed in MIRI. Knockdown of ATF4 exacerbated H/R-induced cell apoptosis and metabolic disturbances. m6A methyltransferase RBM15 modulated the stability and expression of ATF4 mRNA through methylation. Further investigation showed that ATF4 upregulates Sestrin2 to inhibit GSK3β activity, thereby maintaining mitochondrial membrane potential and ATP production, promoting glucose uptake, and enhancing fatty acid oxidation.
    CONCLUSION: This study is the first to reveal the molecular mechanism by which the m6A modified ATF4-Sestrin2/GSK3β signaling axis alleviates MIRI through dual regulation of glucose/lipid metabolism homeostasis and mitochondrial energy supply. It elucidates the bridging role of RBM15-mediated m6A epigenetic modification in this process. These findings provide a new strategy for targeting metabolic reprogramming in MIRI therapy and suggest that ATF4 may serve as an intervention target.
    Keywords:  ATF4; GSK3β; Glucose/lipid metabolism; Myocardial ischemia-reperfusion injury; Sestrin2; m6A modification
    DOI:  https://doi.org/10.1186/s13019-026-04282-8
  47. FEBS Open Bio. 2026 Jun 08.
    From energy provision to protein synthesis: Tunnelling nanotubes as mediators of intercellular metabolic cooperation in cancer.
    Stanislava Martínková, Jan Trnka.
      Tunnelling nanotubes (TNTs) are thin intercellular membrane structures, which enable direct cytoplasmic communication between distant cells. Since their discovery two decades ago, TNTs have been identified in numerous physiological and pathological contexts. This includes cancer, where they contribute to metabolic cooperation, stress adaptation and treatment resistance. Here we summarise the current understanding of the structural and molecular characteristics of TNTs and their cargoes, including nucleic acids, proteins, organelles, pathogens and drugs. We also discuss the cytoskeletal and motor protein machinery underlying TNT biogenesis and cargo transport. Particular attention is also given to mitochondrial transfer and its role in intercellular metabolic cooperation or parasitism, mRNA transfer and its functional effects in recipient cells, and ribosome transfer which suggests intercellular proteosynthetic cooperation. Overall, while we have learned much about TNTs since their identification a little over 20 years ago, there remain significant questions and discoveries still to be made.
    Keywords:  cancer; cytoskeleton; mRNA transfer; mitochondrial transfer; ribosomal transfer; tunnelling nanotubes
    DOI:  https://doi.org/10.1002/2211-5463.70283
  48. J Biol Chem. 2026 Jun 12. pii: S0021-9258(26)02119-8. [Epub ahead of print] 113247
    Exploring the organismal role of UFMylation in development, stress resilience and neurological function in C. elegans.
    Charlotte Sophia Kaiser, Janina Kahl, Emily Jeanne Kouekem, Emma Schröder, Luka Ressmann, Antonio Miranda-Vizuete, Eva Liebau.
      UFMylation is a post-translational modification that conjugates ubiquitin-fold modifier 1 (UFM1) to substrate proteins, regulating fundamental processes including ribosomal homeostasis, the endoplasmic reticulum (ER) stress response and DNA damage repair. While loss-of-function mutations in the UFMylation cascade cause lethality in mammals, they are viable in Caenorhabditis elegans, offering a unique opportunity to investigate its physiological role at the organismal level. We demonstrate that UFM-1 expression progressively increases from larval stages to adulthood, with predominant localization in intestinal cells. Its expression is upregulated during ER stress and autophagy induction, linking it to these pathways. We used CRISPR/Cas9 to create a targeted ufm-1 loss-of-function mutant, which revealed that UFMylation is crucial for lifespan, development and reproduction, with mutants exhibiting increased gonadal dysfunction and sterility. Deletion of ufm-1 enhanced tolerance to various stressors, a resilience potentially arising from a hormetic response to persistent ER stress. Loss of ufm-1 selectively activated the unfolded protein response in the ER but not in mitochondria. Notably, ufm-1 loss exacerbated proteotoxicity in C. elegans muscle-expressed models of protein aggregation, accelerating paralysis and increasing the number and size of amyloid-β, α-synuclein and polyQ aggregates. Furthermore, mutant worms displayed impaired locomotion, including altered swimming patterns resembling those of aging worms, stemming from accelerated, age-dependent sensory neuron dysfunction and structural neurodegeneration.
    Keywords:  C. elegans; UFM1; UFMylation; endoplasmic reticulum stress; neurodegeneration; ubiquitin-fold modifer 1
    DOI:  https://doi.org/10.1016/j.jbc.2026.113247
  49. Anal Chem. 2026 Jun 10.
    Systematic Mapping of Protein Interactions Underlying IL-2 Secretion in Human T Cells.
    Seunghyeon Shin, Frances Rocamora, Nathan E Lewis.
      Protein secretion is crucial in maintaining immune homeostasis, yet the molecular interactions governing this process remain incompletely understood. While transcriptional and post-transcriptional regulation of protein expression is well characterized, the subcellular interactions between secreted proteins and trafficking machinery are less explored. To address this, we systematically mapped protein-protein interactions (PPIs) involved in the secretion of interleukin-2 (IL-2) from human T cells using proximity-based labeling coupled with mass spectrometry. Our analysis revealed significant enrichment of proteins associated with conventional secretory pathways, including ER-to-Golgi transport, protein folding, and vesicle-mediated trafficking. Functional validation demonstrated that several of these proteins are critical for efficient IL-2 secretion, underscoring their participation in cytokine secretion. In addition, time-resolved profiling of PPIs and transcriptomic changes following T-cell stimulation revealed dynamic remodeling of the cytokine secretion machinery, reflecting multilayered regulation at both the protein and gene expression levels. These findings offer a systems-level understanding of IL-2 secretion and identify new molecular components that can be targeted to modulate immune responses. This work provides a framework for dissecting complex secretory processes and has broad implications for therapeutic strategies in immune-related diseases.
    DOI:  https://doi.org/10.1021/acs.analchem.5c05602
  50. Int J Mol Sci. 2026 May 22. pii: 4679. [Epub ahead of print]27(11):
    Molecular Evolution of the Archaeal DNA-Dependent RNA Polymerase: Cooperative Changes in Subunit Composition and Specific Domains of Small Subunits.
    Elena K Shematorova, George V Shpakovski.
      The subunit composition and tertiary structure of DNA-dependent RNA polymerases in archaea, bacteria, and eukaryotes are currently well understood. The single RNA polymerase of archaea resembles the nuclear RNA polymerase II of eukaryotes in its composition and consists of 10-12 subunits. Perhaps the only exception that seems to confirm this rule is the Rpo8 subunit (homologue of the eukaryotic Rpb8), which only some classes of archaea have. The development of metagenomic sequencing has led to a significant revision of the classification system of prokaryotes, in particular to the identification of a number of new Archaea evolutionary lineages. This makes it possible to analyze the subunit composition and structure of RNA polymerase of all currently isolated archaeal phyla. Our analysis shows that the Rpo8 subunit is present only in the RNA polymerase of Archaea species from the Thermoproteota of the Thermoproteati superphylum and from the whole superphylum Promethearchaeati, formerly known as the Asgard. After analyzing the changes in the small Rpo6 subunit (homologue of eukaryotic Rpb6), functionally interacting with Rpo8, we noticed that the largest number of changes in the primary and domain structures of this small subunit occurred in archaeal phyla that lack Rpo8. Shortened forms of Rpo6 without N- or C-terminal regions were observed only in representatives of archaea with an RNA polymerase that does not contain the Rpo8 subunit. Our analysis shows that the changes in Rpo6 are an adaptation of a multisubunit transcription complex to the disappearance of Rpo8. Most likely, the Rpo8 subunit was present in the RNA polymerase of the Last Common Ancestor of Archaea (LCAA) and, in the course of evolution, disappeared in the superphyla Euryarchaeota and Nanobdellati and two divisions of the Thermoproteati superphylum: Bathyarchaeota and Thaumarchaeota.
    Keywords:  Rpo6 subunit; Rpo8 subunit; archaeal RNA polymerase; cooperative changes of small subunits; domain structure; evolution of multi-subunit RNA polymerases; transcripton factors TFB and TFE
    DOI:  https://doi.org/10.3390/ijms27114679
  51. Front Plant Sci. 2026 ;17 1777344
    Role of G3BP1 phosphorylation in the regulation of plant immunity in Arabidopsis thaliana.
    Fatimah Abdulhakim, Aala Abulfaraj, Naganand Rayapuram, Heribert Hirt.
      A central regulator of condensate formation in mammals is the Ras GTPase-activating protein SH3 domain-binding protein (G3BP) family of RNA-binding proteins. In Arabidopsis, G3BP homologs can also form condensates and exhibit diverse expression patterns and subcellular localization. Previously, we identified G3BP1 as a negative regulator of plant immunity that is phosphorylated at Ser257 in vivo. Here, we generated phospho-mimic (G3BP1D) and phospho-dead (G3BP1A) variants and expressed them in Arabidopsis, revealing that the phosphorylation state of G3BP1 affects susceptibility to bacterial infection by influencing ROS production and salicylic acid (SA) accumulation. G3BP1 phosphorylation also influences stomatal immunity by maintaining stomatal opening, thereby modulating pre-invasive defense mechanisms. Furthermore, we show that phosphorylation at Ser257 contributes to the stabilization of G3BP1 by limiting its degradation. Collectively, these findings identify G3BP1 phosphorylation as an important regulatory mechanism in plant immunity and provide new insights into the role of RNA-binding proteins in plant defense responses.
    Keywords:  G3BP1; RNA-binding protein; condensate; phosphorylation; plant immunity; stress granule
    DOI:  https://doi.org/10.3389/fpls.2026.1777344
  52. Daru. 2026 Jun 06. pii: 31. [Epub ahead of print]34(2):
    ALKBH5 promotes the progression of cisplatin-resistant oral squamous cell carcinoma by regulating FOXA1 expression via m6A RNA methylation : Funding.
    Ying Wang, Hui-Xin Yang, Yu-Jia Gu, Mei Tian, Qi-Feng Geng.
       BACKGROUND: Oral squamous cell carcinoma (OSCC) accounts for the vast majority of oral cancer cases. Accumulating evidence has implicated both AlkB homolog 5 (ALKBH5) and forkhead box protein A1 (FOXA1) in the emergence of cisplatin resistance in OSCC. This study aimed to define their functional roles and elucidate the underlying molecular mechanisms.
    METHODS: The expression of ALKBH5, FOXA1, and YTHDF2 was assessed by qPCR and Western blot. Cisplatin-resistant cell lines (H357 CisR and SCC4 CisR) were established via stepwise dose escalation. To investigate key functional phenotypes, a series of assays were employed: CCK-8 for viability, colony formation for proliferation, and Transwell for migration and invasion. Bioinformatics (SRAMP, RM2Target) predicted m⁶A sites on FOXA1 and its binding with ALKBH5, which were validated by MeRIP-qPCR and RIP. FOXA1 mRNA stability was measured by actinomycin D assay.
    RESULTS: ALKBH5 and FOXA1 were upregulated in cisplatin-resistant OSCC, with FOXA1 essential for maintaining oncogenic phenotypes. Bioinformatic and biochemical analyses confirmed FOXA1 as a direct target of ALKBH5. ALKBH5 demethylates FOXA1 mRNA, stabilizing its transcript and enhancing its expression by inhibiting YTHDF2-mediated degradation. Functionally, ALKBH5 overexpression reversed the tumor-suppressive effects of FOXA1 knockdown.
    CONCLUSION: Our study demonstrates that ALKBH5 promotes cisplatin resistance in OSCC through m6A-dependent demethylation of FOXA1 transcripts, highlighting the ALKBH5-FOXA1 axis as a promising therapeutic target for overcoming this resistance.
    Keywords:  ALKBH5; Cisplatin-resistant oral squamous cell carcinoma; FOXA1; YTHDF2; m6A RNA methylation
    DOI:  https://doi.org/10.1007/s40199-026-00614-0
  53. Sci Rep. 2026 Jun 10.
    Excess copper causes repression of global translation in Saccharomyces cerevisiae.
    Amparo Andrés-Bordería, Antonia M Romero, Raquel Sorribes-Dauden, Lola Peñarrubia, María T Martínez-Pastor, Sergi Puig, Ana Perea-García.
      Copper is an essential cofactor for numerous metabolic pathways; however, excess intracellular copper is cytotoxic. In this study, we investigated the consequences of deregulated Cu+ uptake mediated by the high-affinity copper transporter Ctr1 in the model yeast Saccharomyces cerevisiae. Constitutive expression of a carboxy-terminally truncated Ctr1 variant, CTR1(300), resulted in elevated intracellular copper levels, increased oxidative stress, and reduced oxygen consumption, likely due to impairment of iron-sulfur cluster-containing proteins. Notably, CTR1(300)-expressing cells exhibited a pronounced repression of global protein synthesis at very low copper concentrations, a phenotype that was recapitulated in wild-type cells when exposed to higher copper levels. These findings reveal that excessive Cu+ accumulation negatively impacts cellular respiration and translation, identifying protein synthesis as a sensitive target of copper toxicity.
    Keywords:   Saccharomyces cerevisiae ; Copper; Oxidative stress; Toxicity; Translation; Yeast
    DOI:  https://doi.org/10.1038/s41598-026-56882-y
  54. Chem Asian J. 2026 Jun;21(11): e70821
    Quercetin Affects Carcinogenic Phenotype of Breast and Lung Cancer Cells Differentially Through Sterol Regulation Mediated by MALAT1 Perturbation.
    Isha Rakheja, Vishal Bharti, Vandana Singh, Souvik Maiti.
      Targeting MALAT1 in cancer treatment is an attractive strategy due to the undebatable role of this lncRNA in the disease. Small molecules toward this noncoding RNA have, in fact, entered preclinical trials, without resulting in a robust demonstration in favor of their use in therapy. To test the robustness of this method, we asked how aspects of carcinogenesis get affected when knocking down MALAT1 in different cell lines. Using two such cell lines in this study to compare side-by-side, we observed that small molecule quercetin (and its subsequent reduction of MALAT1 lncRNA levels) showed heterogenic effects on carcinogenesis, which is similarly indicated by previous literature. Further, using a combination of cell biology (including the use of 3D tumor spheroids) and bioinformatics, this study is able to pinpoint the probable function of the SREBP1 protein (which showed a significant reduction of around 50%) in affecting carcinogenesis via MALAT1, corroborating earlier reports that link MALAT1 to the sterol regulation axis. This study, in summary, notes that using MALAT1 reduction (using quercetin or otherwise) needs to be very specific in the targeting of cancer cells in order to avoid paradoxical results.
    Keywords:  MALAT1; biology; cancer cell; cancer research; carcinogen; carcinogenesis; phenotype; quercetin; spheroid; sterol
    DOI:  https://doi.org/10.1002/asia.70821
  55. Cancers (Basel). 2026 Jun 02. pii: 1825. [Epub ahead of print]18(11):
    IDH1-Associated m6A Methylation Is Linked to Transcriptomic Heterogeneity in Glioma.
    Syeda Maheen Batool, Hanna Lee, Koushik Muralidharan, Saad Murtaza Khan, Ana K Escobedo, Denalda Gashi, Kesli Faber, Nina R Barretts, Emil Ekanayake, Tiffaney Hsia, Yana Al-Inaya, Aishwarya Kosgi, Julie J Miller, Daniel P Cahill, Gavin P Dunn, Bryan D Choi, Allegra A Petti, Bob S Carter, Leonora Balaj.
      Characterizing the m6A epigenetic landscape is essential for understanding glioma biology, yet transcriptome-wide mapping of these modifications at isoform resolution across specific tumor subtypes has remained limited. Conventional short-read approaches lack the capacity to resolve full-length transcript isoforms or assign m6A modifications to individual transcripts, representing a critical gap in glioma where alternative splicing is pervasive.
    METHODS: We performed direct RNA nanopore sequencing and transcriptome-wide m6A analysis in 14 glioma tumor tissues, including IDH1-mutant astrocytoma, oligodendroglioma, and IDH1 wild-type glioblastoma, enabling isoform-resolved profiling not accessible by conventional short-read approaches. m6A sites were predicted computationally using the m6Anet deep learning framework, which has been independently benchmarked against MeRIP-seq-derived sites, and high-confidence calls were defined at a probability threshold of ≥0.9 and required detection across multiple patients within each subtype.
    RESULTS: IDH1-mutant gliomas showed a higher overall burden of computationally inferred m6A-modified sites, transcripts, and genes than IDH1 wild-type glioblastoma, along with variation in transcript biotypes, regional distribution of m6A sites, and extent of isoform methylation. Differential methylation analysis identified subtype-specific patterns of m6A localization, many of which were observed without corresponding changes in gene-level expression, indicating that m6A variation represents a post-transcriptional regulatory layer not captured by gene-level analysis alone. Integration of gene expression, isoform usage, and m6A status further identified variation in isoform composition and transcript features between astrocytoma and glioblastoma. Analysis of m6A regulators showed subtype-associated expression patterns among readers, writers, and erasers, and exploratory analyses identified isoform-level associations with survival that were not apparent at the gene level.
    CONCLUSIONS: Overall, these data describe subtype-specific patterns of m6A marking and isoform architecture across glioma tissues, derived from computational inference using direct RNA sequencing in a modestly sized cohort and warrant validation by orthogonal methods in larger studies. These findings are consistent with concurrent independent evidence that isoform-specific m6A deposition is evolutionarily conserved across mammals and that long-read isoform resolution reveals transcript diversity in glioma not captured by gene-level analysis. While cohort size and the absence of orthogonal site-level validation suggest that the data require cautious interpretation, this work provides a hypothesis-generating resource and methodological framework for future mechanistic and translational investigation of the glioma epitranscriptome.
    Keywords:  IDH1; N6-methyladenosine; epitranscriptomics; glioma; isoforms; nanopore sequencing
    DOI:  https://doi.org/10.3390/cancers18111825
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