bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–05–03
58 papers selected by
Cédric Chaveroux, CNRS
  1. Investigation of TRMT61B methyltransferase activity on mRNA and its effects on translation.
  2. The nuclear cap-binding complex safeguards stress-resistant protein synthesis and proliferation of stem cells.
  3. G-patch proteins: important regulators of pre-mRNA splicing and ribosome biogenesis.
  4. The integrated stress response in cancer: mechanisms of tumor adaptation and therapeutic targeting.
  5. Cocaine remodels m6A RNA-dependent signaling to drive locomotor plasticity in Drosophila melanogaster.
  6. Genome-wide identification of m6A methyltransferase genes and m6A modification participates in the response to cold stress in rice.
  7. Suppression rather than activation of the integrated stress response (GCN2-ATF4) pathway extends lifespan in the fly.
  8. Temporal gating dictates stress-induced transcript export from the nucleus.
  9. Translational repression of viral RNAs supports persistent arbovirus infection in mosquitoes.
  10. RNA modifications in heart failure: current insights and future directions.
  11. Regulation of multiple paralogs of a small subunit ribosomal protein in Francisella tularensis.
  12. CNOT10 is involved in TTP-mediated AU-rich element containing mRNA metabolism, independent of mRNA decay regulation.
  13. Structural and molecular basis of specialized translation mediated by the ribosome mRNA-binding channel.
  14. The pos-1 3' untranslated region governs germline specification and proliferation to ensure reproductive robustness.
  15. RNAdetector: fast and accurate predictor of RNA type-specific binding residues in protein sequences.
  16. The LARP1 RRM functions as a ribosome responsive regulator of TOP mRNAs.
  17. The selfish ribosome.
  18. The human DEAD-box protein DDX3X regulates host and viral mRNA translation during Sendai Virus infection.
  19. Enzyme-Mediated Covalent Labeling Enables In Situ Imaging of RNA Modification States.
  20. RNA-binding motif proteins as context-dependent regulators of tumor-immune crosstalk, genome stability, and therapeutic vulnerabilities in cancer.
  21. S-Doped Carbon Dot Treatment Alters RNA Processing, Translation, and Protein Degradation Pathways in HeLa Cells.
  22. Regulatory elements on chromatin-associated RNA 15 years beyond RNA epigenetics.
  23. The role of nonsense-mediated mRNA decay in aging.
  24. RNA-binding proteins in the mouse lens: Functional classifications, expression profiling, and interaction studies of Carhsp1 with crystallin mRNAs.
  25. Single-cell profiling reveals pervasive heterogeneity in subcellular RNA localization.
  26. Bidirectional regulation of the ubiquitin-RNA modification axis in cancer.
  27. Involvement Of tRNA Thiolation In uORF-Mediated Translational Regulation During Xylogenesis In Arabidopsis thaliana.
  28. RNA binding protein ZFP36L1 promotes ferroptosis in chronic rhinosinusitis by destabilizing CAMK2A mRNA and impairing mitochondrial quality control.
  29. RNase Z from Deinococcus radiodurans couples tRNA processing with stress-responsive mRNA and sRNA turnover.
  30. Structure-driven function of plant lncRnas: conserved RNA architectures in transcriptional and Post-transcriptional regulation.
  31. METTL3-mediated m6A modification of lncRNA MALAT1 promotes colorectal cancer progression by activating the NF-κB signaling pathway.
  32. Drugs targeting synaptic RNA m6A methylation regulate synaptic transmission and plasticity in the rat hippocampus.
  33. Stage- and stress-specific phosphorylation of ribosomal protein Rps5 (uS7) by Smk1 and Kns1 kinases in Saccharomyces cerevisiae.
  34. Co-translational profiling in the cardiac endothelium in response to LPS-induced inflammation in female mice in vivo: a proof-of-concept approach.
  35. The Effects of Palmitoylethanolamide or Ibuprofen on the Abundance Profile and Synthesis Rate of Proteins in C2C12 Skeletal Myotubes.
  36. Evaluating Ribosomal Protein L19 mRNA as a Biomarker in Ulcerative Colitis: Implications for Severity Assessment.
  37. Structure of the hibernating Francisella tularensis ribosome and mechanistic insights into its inhibition by antibiotics.
  38. Systematic screening of archaeal MazF homologs reveals Tth-MazF1, a versatile, sequence-specific ribonuclease from Thermococcus thioreducens.
  39. Orchestrating innate immunity through RNA editing and helicase activity: ADAR1, dsRNA sensors, and tumor immune evasion.
  40. Schlafen 11 (SLFN11) overexpression and nucleolar localization in response to bortezomib in multiple myeloma.
  41. How Medically Important Antimicrobials Bind to the 30S Ribosomal Subunit in a Bacterial Pathogen.
  42. METTL5 reprograms glycolytic metabolism and promotes non-small cell lung cancer progression by modifying PGAM1.
  43. Structural basis of chaperone mechanisms in cells and the evolutionary emergence of the protein world.
  44. Evaluating the Effect of RNA Interference of Two Heat Shock Proteins (HSPA1L, HSP90B1) in Inducing Apoptosis in Acyrthosiphon Pisum.
  45. The environmental stress response regulates biophysics of the cytoplasm and survival in quiescence.
  46. HNRM: hyperedge neighborhood-based representation for predicting N6-methyladenosine-related regulatory pathways.
  47. Quality control of protein import into mammalian mitochondria.
  48. Advantages and Challenges of G‑Quadruplexes in Regulating Alternative Splicing.
  49. Research on the Inhibition of Cancer Cell Metastasis by Graphene Oxide Suppresses the Translation of the Snail mRNA.
  50. DDX3X-mediated translation of structured cardiac mRNAs is essential for female heart development.
  51. Marine Bioactives in Liver Aging: Mechanistic Insights and Translational Potential.
  52. Polyphosphate modulates the stress-responsive formation of functional RNA-protein condensates in bacteria and mammalian cells.
  53. RNA sensors and actuators for dynamic cellular regulation.
  54. Therapeutic modulation of HIV-1 using miRNAs and lncRNAs: from bench to bedside.
  55. eIF4G2-mediated selective translation of chromatin regulators safeguards adult intestinal stem cell identity and differentiation.
  56. How interdiction of inositol pyrophosphate catabolism perturbs the fission yeast response to phosphate starvation.
  57. Mechanistic Mutational Scanning to Uncover the Secret Life of Proteins.
  58. IGF2BP3 promotes gastric cancer progression by inhibiting ferroptosis through ETV4-mediated regulation of GCH1.
  1. Nucleic Acids Res. 2026 Apr 23. pii: gkag365. [Epub ahead of print]54(8):
    Investigation of TRMT61B methyltransferase activity on mRNA and its effects on translation.
    Dorthy Fang, John M Babich, Ryan Stanton, Isaac W Vock, Kyrillos Abdallah, Mingyi Zhu, Raj Letchuman, Richard Li, Matthew D Simon, Wendy V Gilbert, Sigrid Nachtergaele.
      Despite recent advances in technology to map RNA chemical modifications transcriptome-wide, the distribution of N1-methyladenosine (m1A) in messenger RNA (mRNA) remains contested, hindering a clear understanding of its function. Additionally, the enzyme(s) that installs the majority of reported mRNA m1A sites has yet to be identified. In this study, we characterized TRMT61B, an m1A methyltransferase known to methylate mitochondrial RNAs, but whose sequence preferences have been underexplored. By integrating cellular overexpression of TRMT61B and in vitro methylation of a synthetic pool of diverse human mRNA sequences, we identified a preference for a YMRA consensus motif in single-stranded RNA regions. In these experiments, TRMT61B methylated thousands of novel human mRNA sites, revealing activity on cytosolic mRNAs. We used these novel m1A-modifiable sequences to test the effects of m1A on translation of luciferase reporters and on ribosome recruitment to modified transcripts in the pool. We found that m1A addition can significantly affect translation and ribosome recruitment, but that these effects vary by transcript. Taken together, our results inform future studies of TRMT61B and mRNA modifications, and emphasize that studies of m1A regulation of mRNA must be carried out and interpreted in a highly context-aware manner.
    DOI:  https://doi.org/10.1093/nar/gkag365
  2. Sci Adv. 2026 May;12(18): eaea6630
    The nuclear cap-binding complex safeguards stress-resistant protein synthesis and proliferation of stem cells.
    Seyoun Oh, Jeeyoon Chang, Hodam Jo, Jungwon Yoon, Sung Key Jang, Yoon Ki Kim, Jiwon Jang.
      The integrated stress response (ISR) suppresses global translation while allowing selective synthesis of key regulatory proteins. However, how translation persists during ISR remains unclear. In eukaryotes, the 5'-cap of mRNAs is bound by either the cap-binding complex (CBC) or eIF4E. We show that under stress, CBC-bound mRNAs recruit eIF2A, an alternative initiation factor, to sustain translation when eIF4E-dependent translation is inhibited. Human embryonic stem cells (hESCs), which inherently exhibit ISR, continue proliferating due to a compensatory increase in eIF2A. This increase ensures CBC-dependent translation (CT) of essential cell cycle regulators. Notably, yes-associated protein (YAP), a key proliferation factor, is a major CT target driving stress-resistant stem cell proliferation. Our findings reveal CT as a critical pathway that preserves protein synthesis and proliferation under stress.
    DOI:  https://doi.org/10.1126/sciadv.aea6630
  3. Front Cell Dev Biol. 2026 ;14 1750689
    G-patch proteins: important regulators of pre-mRNA splicing and ribosome biogenesis.
    Laura Olivia Karika, Ingrid Cipakova, Lucia Hronska, Lubos Cipak.
      Pre-mRNA splicing is a fundamental step in eukaryotic gene expression, carried out by the spliceosome. This large and dynamic ribonucleoprotein complex undergoes extensive structural rearrangements during each splicing event. Similarly, ribosome biogenesis is a highly regulated process that requires precise control at every stage, from the transcription of pre-rRNA through its chemical modification and cleavage to the final assembly of mature ribosomal subunits. Central to the regulation of both pre-mRNA splicing and ribosome biogenesis are RNA helicases and their cofactors, notably G-patch proteins. The predominance of G-patch proteins in eukaryotes underscores their evolutionary importance in the increasing complexity of RNA processing and ribosome biogenesis. This review summarizes recent findings on the molecular functions and regulatory roles of various G-patch proteins in the yeasts S. cerevisiae and S. pombe, as well as in humans. Growing evidence indicates that these proteins act as critical cofactors of RNA helicases involved in splicing, facilitating the dynamic transitions required for spliceosome activation, catalysis, and disassembly. Beyond splicing, these proteins also contribute to the regulation of ribosome biogenesis and other aspects of RNA metabolism. Dysregulation or mutation of G-patch proteins have been shown to cause aberrant mRNA maturation, altered splicing patterns, impaired ribosome assembly, and genomic instability. Such perturbations are associated with a range of human diseases, including cancer progression. Despite the essential roles of G-patch proteins in regulating pre-mRNA splicing and ribosome biogenesis, the precise molecular functions and interaction networks of many G-patch proteins remain poorly understood. Future studies aimed at elucidating the mechanisms by which these proteins coordinate RNA processing and ribosome biogenesis are therefore essential. Such investigations may help uncover the molecular basis of G-patch protein-associated diseases and reveal new potential targets for therapeutic intervention.
    Keywords:  G-patch protein; H. sapiens; RNA helicase; S. cerevisiae; S. pombe; pre-mRNA splicing; ribosome biogenesis
    DOI:  https://doi.org/10.3389/fcell.2026.1750689
  4. Biochem Soc Trans. 2026 Apr 29. 54(4): 363-374
    The integrated stress response in cancer: mechanisms of tumor adaptation and therapeutic targeting.
    Elias Maldonado, Emily McIsaac, Josie Ursini-Siegel.
      Cancer cells face continual stressors, which they must overcome to proliferate and survive in the body. Under these conditions, essential biochemical pathways are disrupted, contributing to various stress responses that either promote adaptation and survival or eventual cell death. The evolutionarily conserved integrated stress response (ISR) is a key adaptive mechanism that transiently rewires the transcriptome and translatome in response to various stressors. While the ISR is activated in healthy cells under moderate stress, cancers especially rely on this pathway to overcome harsh conditions experienced during tumor growth and metastasis. We explore the pro-tumorigenic role of the ISR, along with the upstream stress-sensing kinases that activate it. These include protein kinase R-like endoplasmic reticulum kinase, general control non-derepressible 2, double-stranded RNA-dependent protein kinase, and heme-regulated eukaryotic translation initiation factor 2α kinase (HRI), which initiate an ISR in response to diverse stressors by phosphorylating their shared substrate, eukaryotic initiation factor-2α. An in-depth understanding of the pro-survival functions of the ISR and the contexts in which it is pro-tumorigenic is necessary to leverage the ISR as a therapeutic strategy.
    Keywords:  ATF4; Integrated Stress Response; cancer; eIF2alpha
    DOI:  https://doi.org/10.1042/BST20250133
  5. Front Cell Neurosci. 2026 ;20 1810118
    Cocaine remodels m6A RNA-dependent signaling to drive locomotor plasticity in Drosophila melanogaster.
    Ana Filošević Vujnović, Nina Milotić, Bobana Samardžija, Marko Rubinić, Rozi Andretić Waldowski, Alessia Soldano.
      N6-methyladenosine (m6A) is a dynamic RNA modification that regulates RNA stability, processing, and translation and is increasingly recognized as a key modulator of neuronal plasticity. However, how psychostimulant exposure reshapes m6A-dependent regulatory networks across coding and non-coding RNA species remains poorly understood. We investigated the impact of volatilized cocaine (vCOC) exposure on m6A RNA methylation, m6A pathway components, transcriptome, and cocaine-induced locomotor sensitization in Drosophila melanogaster. Acute vCOC administration significantly increased global m6A levels in total and poly(A)-enriched RNA, with a stronger effect in polyadenylated transcripts. This increase occurred without changes in the m6A methyltransferases Mettl3 and Mettl14 transcripts, but was accompanied by robust upregulation of the levels of m6A reader YTHDC and YTHDF transcripts. Genetic and cell-type-specific analyses revealed distinct and context-dependent roles for m6A writers and readers in neurons and glia, with m6A readers being essential for vCOC-induced locomotor sensitization. Integration of RNA-seq and MeRIP-seq demonstrated that vCOC selectively amplifies m6A modification of regulatory and plasticity-associated RNA classes, including mRNAs involved in RNA processing, antisense RNAs, long non-coding RNAs, and transposable element-derived transcripts. In contrast, m6A-modified RNAs shared in CTRL and vCOC were enriched for core metabolic and mitochondrial pathways, such as oxidative phosphorylation. Notably, vCOC increased m6A modification of non-coding RNAs and transposable elements with minimal overlap with control conditions, indicating cocaine-induced engagement of epitranscriptomic regulation at multiple layers of the transcriptome. Together, these findings reveal that cocaine exposure reinforces an m6A-defined regulatory RNA network, spanning coding and non-coding transcripts that is mechanistically linked to m6A reader-dependent behavioral plasticity.
    Keywords:  Drosophila melanogaster; MeRIP-seq; cocaine; locomotor sensitization; m6A RNA modification; non-coding RNA
    DOI:  https://doi.org/10.3389/fncel.2026.1810118
  6. Front Plant Sci. 2026 ;17 1804596
    Genome-wide identification of m6A methyltransferase genes and m6A modification participates in the response to cold stress in rice.
    Shihuan He, Jinxi Xiang, Rui Wang, Zichan Ye, Yue Zhang, Yunxia Fang, Xiaoqin Zhang, Jian Zhang, Xiaoguang Chen, Dawei Xue.
      RNA modification is crucial for the post-transcriptional regulatory mechanism that plays a pivotal role in determining RNA structure and function. Among these, N6-methyladenosine (m6A) represents the most abundant one in eukaryotic mRNA. In plants, m6A modification is catalyzed by a complex comprising multiple methyltransferase components. In this study, bioinformatic analyses were employed to characterize the genes of m6A methyltransferases (m6A writers), including their physicochemical properties, structures, cis-acting elements, chromosomal distributions, phylogenetic relationships, and predicted protein structures. Moreover, qRT-PCR and LC-MS/MS were utilized to investigate the expression patterns of m6A writer genes as well as the m6A abundance in total RNA from rice seedlings under low-temperature conditions. Additionally, m6A me-RIP sequencing was performed to explore changes in the m6A profile of mRNA in rice under cold stress. Collectively, our findings revealed the involvement in the regulation of mRNA m6A modification under cold stress in rice.
    Keywords:  RNA modification; cold stress; m6A; m6A me-RIP sequence; rice
    DOI:  https://doi.org/10.3389/fpls.2026.1804596
  7. Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2518812123
    Suppression rather than activation of the integrated stress response (GCN2-ATF4) pathway extends lifespan in the fly.
    Miriam S Götz, Dan J Hayman, Gracie Adams, Fumiaki Obata, Mirre J P Simons.
      Stress response pathways are emerging as conserved modulators of lifespan. The prevailing hypothesis is that activation of stress-responsive pathways, including the amino acid deprivation arm of the integrated stress response (ISR; the GCN2-ATF4 pathway), is prolongevity. Activation of ATF4 orthologs extends lifespan in Saccharomyces cerevisiae and Caenorhabditis elegans, but its role in other longer-lived organisms remains unclear. We comprehensively tested the role of the GCN2-ATF4 pathway in longevity in the fly (Drosophila melanogaster) for the first time. We used conditional genetic manipulation of dGCN2 and its downstream effector Drosophila ATF4 (crc; dATF4). In contrast to previous studies, we show that overexpression of dGCN2 and dATF4 significantly reduces lifespan, while knockdown (in vivo RNAi) of dATF4 extends lifespan. We confirmed that dATF4 activity was successfully modulated using a fluorescent dATF4 activation reporter. Borrelidin, a tRNA synthetase inhibitor, significantly reduced lifespan in a both dATF4 and diet-dependent manner, independent of microbial load, showing our modulation of dATF4 altered nutrient to ISR signaling. We further conducted long-read RNA sequencing and found that our manipulation of dATF4 changed global transcription in opposite directions, including known ATF4 target genes. Enrichment analysis revealed that dATF4 overexpression may drive metabolic stress, while dATF4 knockdown may upregulate proteostasis and DNA repair pathways. Our work reveals that ATF4 may exhibit a dual, dose-, and context-dependent role in aging. Chronic dATF4 activation is detrimental in flies, while chronic suppression is prolongevity. The GCN2-ATF4 pathway thus qualifies as a modifiable control of lifespan with cross-species relevance.
    Keywords:  aging; borrelidin; integrated stress response; tRNA; transcriptomics
    DOI:  https://doi.org/10.1073/pnas.2518812123
  8. bioRxiv. 2026 Apr 16. pii: 2026.04.14.718555. [Epub ahead of print]
    Temporal gating dictates stress-induced transcript export from the nucleus.
    Noah S Helton, Benjamin Dodd, Stephanie L Moon.
      Prior studies have largely focused on transcriptional and translational control during stress, but how regulated nuclear mRNA export contributes to the stress response remains unresolved. We show that nuclear mRNA export is progressively inhibited during arsenite and heat stress in human cells. In contrast to previous work largely in yeast that suggests nuclear export of stress-induced transcripts is prioritized through sequence-specific mechanisms, we demonstrate that temporal gating determines the nucleocytoplasmic distribution of mRNAs during stress. Using single molecule mRNA imaging and transcriptome-wide analyses, we find the majority of stress-induced mRNAs, including heat shock protein transcripts, accumulate in the nucleus during stress. However, a subset of stress-induced mRNAs, notably HMOX1, JUN , and FOS, escape nuclear retention. mRNAs transcribed early during stress, including those encoding immediate early genes, redox mediators, and protein chaperones, are exported from the nucleus prior to the global inhibition of mRNA export. In contrast, mRNAs transcribed later are retained in the nucleus until stress is resolved. Reporter RNA assays confirm that transcriptional timing determines mRNA export competence. This work reveals that the timing of transcription, rather than transcript-specific sequence features, is the major determinant of nuclear export efficiency of stress-induced transcripts in human cells.
    DOI:  https://doi.org/10.64898/2026.04.14.718555
  9. PLoS Biol. 2026 Apr;24(4): e3003702
    Translational repression of viral RNAs supports persistent arbovirus infection in mosquitoes.
    Marc Talló-Parra, Mireia Puig-Torrents, Gemma Pérez-Vilaró, Sol Ribó Pons, Juana Díez.
      Arboviruses induce acute lytic infection in human cells but establish persistent infection in their mosquito vectors, a viral strategy that is essential for sustained viral transmission. How mosquito cells maintain continuous production of viral progeny without compromising host cell viability remains a fundamental unresolved question. Because arbovirus replication in human cells relies on viral takeover of the host translational machinery, we investigated how translation is regulated during persistent infection in mosquito cells using chikungunya virus (CHIKV) as a model. A temporal analysis of viral RNA translation in RNAi-competent and RNAi-deficient Aedes albopictus cells revealed that persistence was associated with reduced viral protein production resulting from translation repression of viral RNAs. Subcellular localization analyses of the viral protein nsP2 and LC-MS/MS analyses of host tRNAs showed that, in contrast to human cells, CHIKV infection in mosquito cells neither induced nuclear relocalization of viral nsP2 to induce global host mRNA depletion, nor reshaped the tRNA modification landscape to compensate for the suboptimal codon usage of viral RNAs. Together, our results indicate that persistent infection in mosquito cells is characterized by a balanced host-virus translational state, in which limited viral translation is maintained while viral takeover of the host translational machinery is avoided. Notably, translation repression of viral RNAs was also observed during Zika virus (ZIKV) infection, suggesting that this mechanism may represent a general RNAi-independent feature of arbovirus persistence in mosquito cells.
    DOI:  https://doi.org/10.1371/journal.pbio.3003702
  10. Curr Opin Cardiol. 2026 Apr 07.
    RNA modifications in heart failure: current insights and future directions.
    Manisha Deogharia.
       PURPOSE OF REVIEW: Gene expression is regulated at multiple levels beyond genetic and epigenetic modifications of DNA. Even when DNA is accurately transcribed into RNA, transcript abundance often does not correlate with protein levels, underscoring the importance of posttranscriptional regulation. Chemical modifications of RNA occur in both coding and noncoding RNAs and add an additional layer of gene control. More than 170 distinct RNA modifications have been identified across different RNAs in all domains of life. Although the abundant modifications have been investigated, their roles in cardiac biology and heart failure remain incompletely defined. This review discusses the current knowledge of both well characterized and understudied RNA modifications in the heart.
    RECENT FINDINGS: Recent studies highlight context-dependent roles of N6-methyladenosine (m6A), 5-methylcytosine (m5C), N4-acetylcytidine (ac4C), and adenosine-to-inosine (A-to-I) RNA editing in the heart are discussed in this review.
    SUMMARY: RNA modifications constitute a critical regulatory layer that complements transcriptional control and facilitates rapid adaptation to cardiac stress. Dysregulation of m6A, m5C, and A-to-I editing contributes to pathological remodeling and disease progression. However, most RNA modifications remain unexplored in heart failure. Enzymes that write, erase, or read these marks represent promising targets for precision therapeutic strategies.
    Keywords:  N6-methyladenosine, pseudouridine; RNA modification
    DOI:  https://doi.org/10.1097/HCO.0000000000001293
  11. RNA. 2026 Apr 27. pii: rna.080657.125. [Epub ahead of print]
    Regulation of multiple paralogs of a small subunit ribosomal protein in Francisella tularensis.
    Sierra S Schmidt, Alexandra R Farah, Aisling Macaraeg, Daniel Floyd, Hannah S Trautmann, Kathryn M Ramsey.
      Francisella tularensis is a highly infectious human pathogen that must replicate inside macrophage to cause disease. The ribosomes of F. tularensis can incorporate one of three different paralogs for the small ribosomal subunit protein bS21. One of these paralogs positively impacts translation of key virulence genes and promotes intramacrophage replication. Although ribosomal bS21 content influences F. tularensis virulence, the factors that control bS21 paralog production are not well understood. Here, we reveal that all three bS21 proteins influence the transcript abundance of the paralog important for virulence, bS21-2. In contrast, the other bS21 paralogs (bS21-1 and bS21-3) do not affect their own production. We further determined that the leader sequence of the bS21-2 mRNA is sufficient for bS21-mediated repression of mRNA abundance, suggesting that bS21-2 is autogenously regulated. Counterintuitively, we found that in cells lacking bS21-2, the increase in bS21-2-encoding mRNA does not lead to significant increases in protein production. This reduction in translation efficiency suggests that translation of the bS21-2 mRNA is controlled by other factors. Finally, we determined that bS21-2 exerts at least some of its effects on the bS21-2 transcript by decreasing its stability. Together, our findings suggest that F. tularensis may integrate multiple signals into a regulatory network to control the appropriate production of each bS21 paralog, and particularly the paralog important for virulence, bS21-2. This raises the possibility of a regulatory network that can both control ribosome composition in F. tularensis as well as virulence.
    Keywords:  ribosome, Francisella tularensis, ribosomal protein, regulation
    DOI:  https://doi.org/10.1261/rna.080657.125
  12. RNA. 2026 Apr 28. pii: rna.080942.126. [Epub ahead of print]
    CNOT10 is involved in TTP-mediated AU-rich element containing mRNA metabolism, independent of mRNA decay regulation.
    Yukitomo Arao, Jason G Williams, Wi S Lai.
      Tristetraprolin (TTP)/ ZFP36 is an RNA binding protein that is involved in the turnover regulation of target adenylate-uridylate-rich RNA element (ARE) containing mRNAs. AREs are present in the 3'-untranslated region of transcripts expressed from many immediate-early genes, including cytokines and chemokines. It has been demonstrated that TTP-mediated post-transcriptional mRNA decay regulation is crucial for modulating physiological control, particularly in response to inflammatory stimulation. TTP is associated with the CCR4-NOT deadenylation complex through the TTP C-terminus to promote mRNA decay. However, it is not fully understood whether there are additional sites within TTP that contribute to its function through interacting with other factors. We analyzed the functionality of the unique tryptophan residues located in the TTP N-terminus using a cell-based assay system that consists of a tetracycline-responsive CMV promoter-driven, intron-inserted luciferase (LUC). This system enabled us to analyze TTP activity during both the early phase and the steady-state phase of gene expression, as well as in the post-transcriptional mRNA decay following the treatment of tetracycline analogs. Meanwhile, we identified putative TTP associates using a proximity labeling method. We found that tryptophan residues in the TTP N-terminus together with CNOT10, a component of the CCR4-NOT complex, were involved specifically in the reduction of the ARE-containing LUC mRNA level during the early phase of gene expression. However, they were not involved in the decay of LUC mRNA in the steady-state phase. We propose a novel post-transcriptional TTP functionality in the reduction of ARE-containing mRNA level, which differs from the well-characterized mRNA decay activity.
    Keywords:  CCR4-NOT complex; Post-transcriptional regulation; Tristetraprolin; ZFP36
    DOI:  https://doi.org/10.1261/rna.080942.126
  13. Nat Commun. 2026 Apr 29.
    Structural and molecular basis of specialized translation mediated by the ribosome mRNA-binding channel.
    Davide Fraticelli, Disha Gajanan Hiregange, Benjamin Weiss, Ariel Ogran, Tal Havkin-Solomon, Irene Martinez Roman, Anat Bashan, Ada Yonath, Rivka Dikstein.
      The ribosome mRNA channel is central to translation, yet its role in regulatory mechanisms remains unclear. Using cryo-EM of human ribosomal complexes bound to Kozak and TISU mRNAs from wild-type (WT) and RPS26/eS26 mutant (RPS26dC) cells, we demonstrate that both RPS26/eS26 and mRNA adopt distinct conformations, explaining the opposing effects of RPS26dC on their activity. Translatome studies of WT and RPS26dC reveal AUG-context-dependent changes in 48S and 80S initiation complexes and slower scanning. Downregulated mRNAs are enriched for specific AUG-upstream nucleotides and a -1-cytosine contacting 18S rRNA G1207, an interaction lost in RPS26dC. Strongly affected transcripts include replication-dependent histones, which, despite short 5'UTRs and suboptimal Kozak, exhibit robust translation activity that is RPS26/eS26-dependent. We identify a translational enhancer in the H2B 5'UTR (-16 to -9) overlapping predicted RPS26/eS26-binding sites, with a distinct ribosome-bound conformation. Exploiting these features, we engineered a high-efficiency translational cassette with minimal leaky scanning. These findings underscore the role of the ribosome's mRNA channel in selective translation and its therapeutic potential.
    DOI:  https://doi.org/10.1038/s41467-026-72263-5
  14. PLoS Genet. 2026 Apr;22(4): e1012129
    The pos-1 3' untranslated region governs germline specification and proliferation to ensure reproductive robustness.
    Haik V Varderesian, Juliet N Utaegbulam, Hannah E Brown, Beverly Ramirez, Melina Velcani, Sean P Ryder.
      During fertilization, haploid gametes combine to form a zygote. The male (sperm) and female (oocyte) gametes contribute a similar amount of DNA, but the oocyte contributes nearly all the cytoplasm. Oocytes are loaded with maternal mRNAs thought to be essential for embryonic patterning after fertilization. A conserved suite of RNA-binding proteins (RBPs) regulates the spatiotemporal translation and stability of maternal mRNAs. POS-1 is a CCCH-type tandem zinc finger RBP expressed in fertilized Caenorhabditis elegans zygotes from maternally supplied mRNA. POS-1 accumulates in the posterior of the embryo where it promotes posterior cell fate. Here, we show that the pos-1 3' untranslated region (UTR) is essential for POS-1 patterning and contributes to maximal reproductive fecundity. We engineered a pos-1 mutant where most of the endogenous pos-1 3'UTR was removed using CRISPR genome editing. Our results show that the 3'UTR represses POS-1 expression in the maternal germline but increases POS-1 protein levels in embryos after fertilization. In a wild-type background, POS-1 repression via the 3'UTR has little impact on fertility. In a sensitized background, the deletion mutant has a complex pleiotropic phenotype where most adult homozygous progeny lack either one or both gonad arms. Most phenotypes become more penetrant at elevated temperature. Together, our results support an emerging model where the 3'UTRs of maternal transcripts, rather than being essential, contribute to reproductive robustness during stress.
    DOI:  https://doi.org/10.1371/journal.pgen.1012129
  15. Nucleic Acids Res. 2026 Apr 23. pii: gkag394. [Epub ahead of print]54(8):
    RNAdetector: fast and accurate predictor of RNA type-specific binding residues in protein sequences.
    Gang Hu, Kui Wang, Ajay Arya, Lukasz Kurgan.
      Proteins interact with several RNA types to facilitate a broad spectrum of cellular functions. However, the underlying interaction data are sparse, and existing methods for predicting RNA-binding residues (RBRs) in protein sequences are almost exclusively RNA type-agnostic, limiting their utility. To this end, we introduced RNAdetector, a sequence-based method that accurately predicts messenger RNA-, ribosomal RNA-, small nuclear RNA (snRNA)-, and transfer RNA-binding residues and type-agnostic RBRs. RNAdetector employs an innovative deep transformer network architecture and transfer learning, which together produce a large boost to predictive performance and minimize cross-predictions, defined as incorrectly predicting wrong types of RBRs. Moreover, our design has a low computational footprint and produces accurate predictions in about 9 s per protein, facilitating analysis of large collections of proteins. A comparative evaluation on a low-similarity test dataset showed that RNAdetector provided substantially more accurate RNA-type-specific predictions, a much shorter runtime, additionally covered snRNA, and significantly reduced cross-predictions compared to the only other RNA-type-specific predictor that is cross-prediction prone. Moreover, we empirically showed that RNAdetector's predictions of type-agnostic RBRs are modestly more accurate than those generated by several representative predictors of RNA-type-agnostic RBRs and RNA-binding proteins. RNAdetector is available as a convenient web server at http://biomine.cs.vcu.edu/servers/RNAdetector/.
    DOI:  https://doi.org/10.1093/nar/gkag394
  16. bioRxiv. 2026 Apr 19. pii: 2026.04.18.719249. [Epub ahead of print]
    The LARP1 RRM functions as a ribosome responsive regulator of TOP mRNAs.
    James A Saba, Phoebe E White, A Maxwell Burroughs, L Aravind, Rachel Green.
      The synthesis of ribosomes in metazoans is an essential process that is dysregulated in disease. Previous studies implicate La-related protein 1 (LARP1) in binding inactive ribosomes and in repressing Terminal OligoPyrimidine motif mRNAs (TOPs), which encode ribosomal proteins. While the molecular details of LARP1 binding to the ribosome and to TOP mRNAs are deciphered, the mechanistic link between these two activities is not understood. Here, we show that ribosome binding is an essential step in LARP1-mediated TOP repression. LARP1's ribosome binding region is part of a previously unrecognized RNA recognition motif (RRM) domain, which in turn directly interacts with its TOP-binding HEAT repeat domain. Remarkably, ribosome binding is both sufficient in vitro and required in cells for LARP1 to bind, repress, and stabilize TOPs via unfolding and remodeling of the RRM domain. Disrupting the coordinated architecture of these domains by mutating the RRM constitutively represses TOPs and compromises cell fitness. Together, these data reveal a general ribosome-sensing function of LARP1, orchestrated through the unique coordinating role of its RRM, which tunes the synthesis of ribosomal proteins to cellular demand for ribosomes.
    DOI:  https://doi.org/10.64898/2026.04.18.719249
  17. ArXiv. 2026 Feb 27. pii: arXiv:2602.23268v2. [Epub ahead of print]
    The selfish ribosome.
    Mart Krupovic, Eugene V Koonin.
      The ribosome is responsible for protein synthesis in all cells, and is the largest energy consumer in the cell. We propose that the ribosome originated as a mutualistic symbiont of an RNA-dependent RNA polymerase ribozyme, supplying peptides that enhanced replication. As life transitioned from the RNA to the RNA-protein world, autonomous replicators became irreversibly addicted to the ribosome for producing replication proteins. Subsequent evolution is construed as a ribosomal takeover, whereby the ribosome evolved to consume most of the resources of the cell, while other cellular componentry ensured the propagation of the ribosome. Under this perspective, the ribosome is the ultimate biological selfish element.
  18. bioRxiv. 2026 Mar 09. pii: 2026.03.08.707086. [Epub ahead of print]
    The human DEAD-box protein DDX3X regulates host and viral mRNA translation during Sendai Virus infection.
    Cathal S Ryan, Dimitrios G Anastasakis, Ahsan H Polash, Elizabeth Sitko, Markus Hafner, Martina Schröder.
      DDX3X is a multifunctional DEAD-box RNA helicase with important roles in translation initiation and antiviral innate immune signaling, yet it is currently unknown whether viral infection affects its interactions with host RNAs. Here, we define the transcriptome-wide binding landscape of endogenous DDX3X in Sendai virus-infected human cells using PAR-CLIP. We show that DDX3X maintains its preference for GC-rich, highly structured 5'UTR regions during infection, but acquires a distinct set of infection-induced targets, including IFNB1 and multiple interferon-stimulated genes. We demonstrate that DDX3X directly binds the IFNB1 5'UTR and promotes its translation, establishing a previously unrecognized post-transcriptional mechanism contributing to DDX3X-dependent IFN-β production. We also evaluated DDX3X's binding to SeV RNAs and concluded that DDX3X is likely not actively recruited by SeV or has a significant effect on its viral life cycle. Our findings add a novel dimension to DDX3X's involvement in anti-viral immunity with implications for further therapeutic development of DDX3X inhibitors.
    DOI:  https://doi.org/10.64898/2026.03.08.707086
  19. J Am Chem Soc. 2026 Apr 28.
    Enzyme-Mediated Covalent Labeling Enables In Situ Imaging of RNA Modification States.
    Andrew H Ryu, Neal K Devaraj.
      Post-transcriptional tRNA modifications are regulators of gene expression, yet their spatial organization and dynamic regulation remain poorly understood, because methods to track tRNA modification status inside cells are lacking. Sequencing and biochemical approaches provide population-level readouts but typically require RNA extraction, eliminating spatial information and obscuring cell-to-cell heterogeneity. Here, we report a chemoenzymatic RNA fluorescent labeling strategy that enables the imaging of a specific tRNA modification state in mammalian cells. Our method relies on the catalytic selectivity of the bacterial enzyme tRNA guanine transglycosylase (TGT) to covalently incorporate fluorophore-conjugated preQ1 analogues into q-cognate tRNAs only when they lack queuine, a unique hypermodified base that influences translation, stress responses, and mammalian physiology. Because queuine-modified tRNAs are not substrates for transglycosylation, fluorophore incorporation directly reports the hypomodification status. Queuine-hypomodified tRNAs are selectively visualized with subcellular resolution in fixed cells. Using this approach, we track queuine incorporation and loss kinetics across cell lines, analyze genetic factors that control modification, and resolve differences between cytosolic and mitochondrial tRNA populations. Beyond queuine, this work demonstrates a strategy for converting the endogenous RNA modification state into a covalent fluorescent readout, providing a chemical framework for spatial analysis of RNA modifications in intact cells.
    DOI:  https://doi.org/10.1021/jacs.6c03719
  20. Front Immunol. 2026 ;17 1797535
    RNA-binding motif proteins as context-dependent regulators of tumor-immune crosstalk, genome stability, and therapeutic vulnerabilities in cancer.
    Jun Zhang, Yunfeng Li, Hailing Han, Bingya Zhang.
      Cancer progression relies on dynamic post-transcriptional RNA regulation to enable phenotypic plasticity, immune evasion, and therapeutic resistance. RNA-binding motif (RBM) proteins emerge as pivotal orchestrators of these processes, modulating splicing, mRNA stability, and translation in a context-dependent manner across malignancies. This article provides a narrative mechanistic synthesis of published evidence and does not report original cohort construction or predictive-model development. Here, we review how RBM-driven RNA programs promote proliferative advantages through splicing rewiring, transcript stabilization via m6A modifications, and dual oncogenic/tumor-suppressive roles. We highlight RBM contributions to epithelial-mesenchymal transitions (EMT) and metastatic niche adaptation, including isoform-specific regulation of EMT effectors and metabolic reprogramming. Furthermore, RBMs shape tumor-immune dynamics by triggering innate immune activation through RNA misprocessing, suppressing adaptive immunity through PD-L1 upregulation, and remodeling the immunosuppressive microenvironment via cytokine and metabolic circuits. RBMs also integrate RNA processing with the choice of DNA repair pathways and genotoxic stress responses, underpinning resistance to chemotherapy and radiotherapy. Finally, pharmacological targeting of RBMs, such as RBM39 degradation via molecular glues like indisulam, exploits splicing dependencies to collapse oncogenic states and overcome resistance. These insights position RBMs as therapeutic nodes for precision immuno-oncology, with implications for biomarker-driven strategies in splicing-addicted tumors.
    Keywords:  RNA-binding motif; epithelial–mesenchymal transitions; immuno-oncology; immunosuppressive microenvironment; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2026.1797535
  21. Curr Issues Mol Biol. 2026 Mar 26. pii: 349. [Epub ahead of print]48(4):
    S-Doped Carbon Dot Treatment Alters RNA Processing, Translation, and Protein Degradation Pathways in HeLa Cells.
    Katarina Davalieva, Vanja Ralić, Gjorgji Bozhinovski, Branislava Gemović, Maja D Nešić, Lela Korićanac, Tanja Dučić, Manuel Algarra, Iva A Popović, Milutin Stepić, Marijana Petković.
      Carbon dots offer excellent physico-chemical properties and biocompatibility for cancer theranostics systems, either as therapeutic agents themselves, or as potential drug carriers. It is, however, postulated that the drug carrier affects the mechanism of action and intracellular target molecules of a drug. Therefore, in the present study, we systematically evaluated protein alterations in HeLa cervical cancer cells after treatment with sulfur-doped carbon dots (S-CDs). Synchrotron Radiation μFTIR spectroscopy and label-free LC-MS/MS proteomics integrated with bioinformatics were used to assess molecular changes. μFTIR revealed a shift and increased intensity of α-helices, indicating structural changes in proteins as a result of the interaction between S-CDs and cells. Proteomic analysis identified 122 statistically significant (p ≤ 0.05) proteins with increased abundance and 61 with decreased abundance following S-CD exposure, many of which possess high α-helix content, consistent with μFTIR findings. Functional analyses showed that up-regulated proteins were enriched in molecular adaptor, transporter, and transcription regulator activities, particularly those involved in RNA metabolism and translation. Down-regulated proteins were dominated by protein-modifying enzymes and cytoskeletal components. Pathway enrichment analysis indicated alterations in mRNA processing, ribosomal pathways, translation factors, aminoacyl-tRNA biosynthesis, and proteasome degradation. Key hub proteins included ribosomal proteins and translation initiation factors. S-CD treatment led to opposite regulation of many proteins compared to their regulation in untreated HeLa cells including down-regulation of ribosomal proteins (RPS27L, RPS19, and RPS5), aminoacyl-tRNA biosynthesis proteins (IARS1, LARS1, and MARS1), and proteasome degradation proteins (PSMD2, PSMD3, and PSMD11), which aligns with the observed cytotoxic effect of S-CDs on cervical cancer cells. Overall, these results highlight significant proteomic and structural protein changes induced by S-CDs and support their potential for cervical cancer treatment, warranting further investigation of this nanomaterial's biological applications.
    Keywords:  S-doped carbon dots; bioinformatics; proteomics; ribosomes; µFTIR
    DOI:  https://doi.org/10.3390/cimb48040349
  22. Nat Chem Biol. 2026 Apr 28.
    Regulatory elements on chromatin-associated RNA 15 years beyond RNA epigenetics.
    Xiaoyang Dou, Chuan He.
      Chemical modifications on RNA represent an additional regulatory layer of gene expression analogous to epigenetic marks on DNA and histones. Over the past decade, the fundamental mechanisms of N6-methyladenosine and other mRNA modifications have been extensively characterized, establishing their roles in nearly all aspects of RNA metabolism with broad implications for physiological and pathological processes. These advances lay the groundwork for future therapeutic approaches targeting mRNA modification pathways. By contrast, emerging evidence indicates that RNA methylation on chromatin-associated RNAs (caRNAs) intersects with chromatin regulators to modulate chromatin state and transcription, adding a new dimension to epigenetic regulation with biological significance. Here we summarize established principles of post-transcriptional RNA modifications and their therapeutic potential, highlight the rapidly developing chromatin-related functions of RNA modifications as regulatory elements on caRNAs and discuss future directions that emphasize the need to investigate additional regulatory elements on these RNAs in shaping gene expression programs.
    DOI:  https://doi.org/10.1038/s41589-026-02207-z
  23. J Mol Biol. 2026 Apr 28. pii: S0022-2836(26)00203-2. [Epub ahead of print] 169830
    The role of nonsense-mediated mRNA decay in aging.
    Eunseok Kang, Hyunwoo C Kwon, Seung-Jae V Lee.
      Aging is a complex biological process that gradually increases vulnerability to death and susceptibility to age-related diseases. Emerging evidence indicates that nonsense-mediated mRNA decay (NMD), a conserved RNA surveillance pathway in eukaryotes, plays a crucial role in the regulation of aging and longevity. In this manuscript, we discuss the role of key NMD factors in aging at the cellular and organismal levels. We highlight the age-related decline in NMD activity in various organisms, which may increase the production of truncated proteins. In addition, we discuss how NMD contributes to longevity and the prevention of cellular senescence. Our review provides valuable information on the molecular mechanisms by which NMD regulates aging, and enhances our understanding of how mRNA quality control, especially NMD, can be utilized for contributing to healthy longevity in humans.
    DOI:  https://doi.org/10.1016/j.jmb.2026.169830
  24. Dev Biol. 2026 Apr 28. pii: S0012-1606(26)00098-9. [Epub ahead of print]
    RNA-binding proteins in the mouse lens: Functional classifications, expression profiling, and interaction studies of Carhsp1 with crystallin mRNAs.
    Danielle Rayêe, Dong-Woo Hwang, William K Chang, Ilana N Karp, Sarah Y Coomson, Yilin Zhao, Teresa Bowman, Salil A Lachke, Robert H Singer, Carolina Eliscovich, Ales Cvekl.
      RNA-binding proteins (RBPs) are critical regulators of mRNAs controlling all processes such as RNA transcription, transport, localization, translation, mRNA:ncRNA interactions, and decay. Cellular differentiation is driven by temporally and spatially regulated expression of proteins needed for the optimal function of individual cells, tissues and organs. Lens fiber cell differentiation is marked by high levels of expression of crystallin genes encoding critical proteins for lens transparency and light refraction. Herein we performed proteomic and transcriptomic analyses of RBPs in differentiating mouse lenses to identify the most abundant RBPs and establish dynamic changes of their expression in differentiating lenses. Expression analyses showed highly abundant RBPs, including Carhsp1, Igf2bp1/ZBP1, Ybx1, Pabpc1, Ddx39, and Rbm38. Binding sites of Carhsp1, the most abundant lens RBP, were predicted in various crystallin and β-actin mRNAs. Immunoprecipitations using Carhsp1-specific antibodies confirmed interactions of Carhsp1 with crystallin mRNAs in newborn lens. A combination of single molecule RNA FISH (smFISH) and immunofluorescence was used to probe in vivo interactions of Carhsp1 with αA-, αB-crystallin, and β-actin mRNAs in cytoplasm and nucleoplasm of cultured mouse lens epithelial cells. These experiments favor a working model of direct association of Carhsp1 mediated by multiple candidate binding sites within both αA-, αB-crystallin mRNAs. Together, these results open new avenues to perform comprehensive genetic, cell, and molecular biology studies of individual RBPs in the lens.
    Keywords:  Carhsp1; RNA-binding proteins; crystallin mRNA; lens; mRNA stability; single molecule fluorescence.RNA hybridization
    DOI:  https://doi.org/10.1016/j.ydbio.2026.04.017
  25. bioRxiv. 2026 Feb 06. pii: 2026.02.04.703776. [Epub ahead of print]
    Single-cell profiling reveals pervasive heterogeneity in subcellular RNA localization.
    Xiaojuan Fan, Markus Hafner.
      Subcellular RNA localization is a fundamental layer of gene regulation, yet its heterogeneity across individual cells remains poorly understood. Here, we introduce the RNA Localization Profiler (RLP), a proximity-based RNA-editing strategy that maps compartment-specific RNAs in living cells. Across the cytoplasm, endoplasmic reticulum (ER), and plasma membrane, RLP identifies robust and highly specific RNA localization programs linked to translation and membrane organization. Single-cell RLP (scRLP) reveals that individual cells harbor roughly 5,000-7,000 cytoplasmic RNAs, with <10% associated with the ER. These measurements uncover pervasive subcellular heterogeneity in RNA localization that is undetectable by bulk assays. Spatial RNA patterns define an orthogonal axis of cell-state identity that is independent of gene expression. For example, ZWINT mRNA relocalizes to the cytoplasm in a cell cycle-dependent manner. These findings establish heterogeneous levels of subcellular RNA localization as a variable dimension of intracellular organization and cell identity.
    DOI:  https://doi.org/10.64898/2026.02.04.703776
  26. Front Oncol. 2026 ;16 1761698
    Bidirectional regulation of the ubiquitin-RNA modification axis in cancer.
    Kailang Li, Lingling Bao, Bitao Jiang, Xiaofeng Jin.
      RNA modifications, dynamically regulated by RNA-modifying proteins (RMPs) acting as "writers", "erasers", and "readers", play pivotal roles in governing gene expression and cellular fate. These modifications are also intimately linked to cancer initiation and progression. Dysregulation of RMPs in tumors disrupts RNA modification homeostasis, thereby promoting cancer progression through enhanced proliferation, metastasis, and immune evasion. The ubiquitination system serves as critical regulator of RMP stability and activity, which in turn shapes the cancer epitranscriptome. Conversely, RNA modifications feedback into ubiquitination pathways by modulating the stability and translation of mRNAs encoding ubiquitination-related factors. This bidirectional crosstalk between RMPs and ubiquitination forms a sophisticated regulatory network that enhances cancer adaptability. Notably, emerging therapeutic strategies aimed at targeting RMP ubiquitination have shown promising potential. In this review, we systematically examine the bidirectional regulatory axis between ubiquitination and RMPs in cancer pathogenesis. We first outline how ubiquitination controls RMP activity and the consequent epitranscriptomic alterations and then explore how RNA modifications reciprocally influence ubiquitination pathways. Building on this mechanistic foundation, we evaluate current therapeutic approaches targeting the ubiquitination-epitranscriptome axis and highlight key knowledge gaps in our understanding of this dynamic regulatory network. Finally, we propose future research directions to fully decode the therapeutic potential of this dynamic regulatory network in oncology, thereby providing novel perspectives on cancer development.
    Keywords:  RNA modifications; cancer; epitranscriptomics; network; ubiquitination
    DOI:  https://doi.org/10.3389/fonc.2026.1761698
  27. Plant Cell Physiol. 2026 Apr 28. pii: pcag055. [Epub ahead of print]
    Involvement Of tRNA Thiolation In uORF-Mediated Translational Regulation During Xylogenesis In Arabidopsis thaliana.
    Yuichi Nishii, Daichi Araki, Mitsuru Saraumi, Taku Takahashi.
      Post-transcriptional modification of tRNAs is an important mechanism for regulating translation efficiency and cellular homeostasis, yet its contribution to upstream open reading frame (uORF)-mediated translational control remains largely unexplored. In this study, we investigated the role of tRNA thiolation in thermospermine-dependent regulation of xylem development in Arabidopsis thaliana. Using a suppressor screen of the thermospermine-deficient mutant acaulis5 (acl5), which exhibits dwarfism and excessive xylem differentiation, we identified suppressor-of-acl502 (sac502) as a recessive loss-of-function allele of CTU2, a gene encoding a key enzyme in the biosynthesis of the wobble uridine modification 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U). Mutations in other components of the same modification pathway, including ROL5 and TRM9, similarly suppressed the acl5 phenotype. Translational analyses using 5' leader-GUS reporter constructs revealed that the ctu2 mutation did not enhance translation of the mRNA containing a thermospermine-responsive uORF of SAC51, but instead significantly reduced translation of that of SACL3, a member of the SAC51 family, and that of LONESOME HIGHWAY (LHW), which contains another conserved uORF in the 5' leader region. Polysome profiling further demonstrated decreased association of SACL3 and LHW mRNAs with actively translating ribosomes in ctu2. Genetic interaction analyses supported the conclusion that the suppression of excessive xylem formation in acl5 by ctu2 is attributable to reduced LHW activity. In addition, ctu2 mutants displayed increased sensitivity to exogenous thermospermine, resembling the response of lhw mutants. Together, our results reveal that tRNA thiolation contributes to uORF-mediated translational regulation of key developmental regulators and identify tRNA modification as an important regulatory layer controlling vascular development.
    Keywords:  Arabidopsis; mRNA translation; tRNA thiolation; thermospermine; uORF
    DOI:  https://doi.org/10.1093/pcp/pcag055
  28. Clin Transl Med. 2026 May;16(5): e70661
    RNA binding protein ZFP36L1 promotes ferroptosis in chronic rhinosinusitis by destabilizing CAMK2A mRNA and impairing mitochondrial quality control.
    Jiayi Xiong, Shihan Zhang, Chunhua Li, Yufeng Ai, Xinru Liu, Yuxiang Liu, Hongbing Liu.
       BACKGROUND: RNA-binding proteins (RBPs) and ferroptosis have been demonstrated to play important roles in the progression of chronic rhinosinusitis (CRS). However, the regulatory mechanisms underlying the interaction between RBPs and ferroptosis in CRS, particularly regarding mitochondrial metabolism, remain elusive.
    METHODS: Hub genes correlated with RBP-related genes, ferroptosis-related genes and mitochondrial-related genes were identified by integrated bioinformatics analysis. CRS in vivo models were constructed, clinical samples were collected, and mechanistic analyses were performed for validation.
    RESULTS: ZFP36L1 was identified as the hub gene associated with CRS development. In vivo experiments demonstrated that ZFP36L1 directly binds to the 3'-untranslated region of CAMK2A mRNA and promotes its degradation through AU-rich element recognition. ZFP36L1 knockout in CRS mouse models restored CAMK2A expression and significantly attenuated ferroptosis markers, reactive oxygen species accumulation and mitochondrial dysfunction. Rescue experiments revealed that CAMK2A knockdown reversed the protective effects of ZFP36L1 depletion on ferroptosis and mitochondrial quality control. Clinical samples confirmed that ZFP36L1 expression was inversely correlated with CAMK2A levels, and both were associated with disease severity.
    CONCLUSION: This study identifies ZFP36L1-CAMK2A as a contributory regulatory mechanism in CRS pathogenesis. ZFP36L1 promotes ferroptosis by destabilizing CAMK2A mRNA, leading to mitochondrial dysfunction and subsequent epithelial cell death. These findings provide new mechanistic insights into CRS progression and identify potential therapeutic targets.
    HIGHLIGHTS: ZFP36L1 is identified as a key driver gene in chronic rhinosinusitis (CRS) progression via integrated bioinformatics analysis. ZFP36L1 promotes ferroptosis by binding to and destabilizing CAMK2A mRNA through AU-rich elements in its 3'-UTR. Genetic knockout of ZFP36L1 attenuates ferroptosis and restores mitochondrial quality control in CRS models. Clinical validation confirms the ZFP36L1-CAMK2A axis correlates with disease severity and represents a potential therapeutic target.
    Keywords:  CAMK2A; RNA‐binding proteins; ZFP36L1; chronic rhinosinusitis; ferroptosis; mitochondrial quality control
    DOI:  https://doi.org/10.1002/ctm2.70661
  29. Biochem Biophys Res Commun. 2026 Apr 27. pii: S0006-291X(26)00577-2. [Epub ahead of print]820 153813
    RNase Z from Deinococcus radiodurans couples tRNA processing with stress-responsive mRNA and sRNA turnover.
    Palak Middha, Tanmay Dutta.
      RNase Z is a conserved metallo-dependent endoribonuclease that catalyzes the 3'-end processing of precursor tRNAs. Although its canonical role in tRNA maturation is well established, its involvement in RNA turnover during stress responses remains poorly understood in many bacteria. In this study, we characterized the biochemical properties and regulatory functions of RNase Z from Deinococcus radiodurans (DrRNase Z). The rnz gene was cloned, overexpressed in Escherichia coli, and the recombinant enzyme was purified to homogeneity. ICP-MS analysis revealed that DrRNase Z coordinates two Zn2+ ions per monomer and exhibits Zn2+-dependent phosphodiesterase activity. Kinetic analysis demonstrated catalytic parameters comparable to other RNase Z homologues. Using in vitro-transcribed substrates, DrRNase Z efficiently processed precursor tRNAArg by endonucleolytic removal of extra nucleotides downstream of the 3'-CCA sequence, while mature tRNA remained resistant to cleavage. Interestingly, rnz transcript levels decreased significantly following γ-irradiation or oxidative stress. In vitro assays further showed that DrRNase Z cleaves the oxidative stress-inducible katA mRNA and the stress-responsive small RNA IGR_1612, which enhances cellular growth under oxidative stress when ectopically expressed. These findings indicate that DrRNase Z not only participates in tRNA maturation but also contributes to the turnover of stress-induced mRNAs and sRNAs, thereby helping restore RNA homeostasis in D. radiodurans following stress exposure.
    Keywords:  RNA homeostasis; RNA metabolism; RNase Z; Stress-sensitive ribonucleases
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153813
  30. RNA Biol. 2026 Apr 27.
    Structure-driven function of plant lncRnas: conserved RNA architectures in transcriptional and Post-transcriptional regulation.
    Yanqi Shen, Qianli Dong, Yiliang Ding, Huakun Zhang.
      Long noncoding RNAs (lncRNAs) have emerged as critical regulators of plant development, physiology, and environmental stress adaptation. Despite exhibiting limited primary sequence conservation across the plant kingdom, emerging evidence underscores that plant lncRNA functionality is encoded at the level of RNA secondary structure, facilitating diverse modes of structure-mediated gene regulation. In this review, we synthesize recent advances in elucidating the structural conservation, and molecular functions of plant lncRNAs. We further discuss their expanding regulatory repertoire and assess their potential utility as innovative molecular tools for crop improvement.
    Keywords:  Long noncoding RNA (lncRnas); RNA secondary structure; RNA stability; plant, transcription; translation
    DOI:  https://doi.org/10.1080/15476286.2026.2664959
  31. J Transl Med. 2026 Apr 25.
    METTL3-mediated m6A modification of lncRNA MALAT1 promotes colorectal cancer progression by activating the NF-κB signaling pathway.
    Shuangming Lin, Hao Zeng, Xueyi Xue, Baodong Liao, Hao Lin, Yuhui Wang, Dongbo Xu.
       BACKGROUND: Colorectal cancer (CRC), a prevalent malignancy of the digestive system, is often characterized by poor patient prognosis due to high rates of recurrence and metastasis. N6-methyladenosine (m6A) modification represents a crucial epigenetic mechanism regulating RNA (including lncRNAs) function and is increasingly implicated in tumor progression. However, the underlying regulatory mechanism of m6A modification in CRC pathogenesis remain incompletely understood.
    METHODS: We first integrated bioinformatic analysis data, which revealed a significant positive correlation and co-enrichment of methyltransferase-Like 3 (METTL3) and the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in a high-risk prognostic signature. Functional validation included in vitro assessments of cellular proliferation, migration, invasion, apoptosis, and m6A methylation levels following METTL3 or MALAT1 suppression, alongside in vivo xenograft tumor models to evaluate the effects of a METTL3 inhibitor on tumor growth dynamics and m6A modification levels. Finally, mechanistic profiling was conducted to dissect NF-κB pathway activity.
    RESULTS: METTL3 and MALAT1 were markedly upregulated in CRC tissues and cell lines. Molecular docking identified trihydroxy methylcyclohexane aminoglycoside (TMA) as a high-affinity METTL3-binding compound. Inhibition of METTL3 or MALAT1 significantly impaired cellular proliferation, migration, and invasion, while promoting apoptosis. RNA immunoprecipitation quantitative PCR (RIP-qPCR) and RNA stability assays established that METTL3 maintains MALAT1 stability via m6A modification. In vivo, suppression of METTL3 potently inhibited xenograft tumor growth without observable toxicity. Western blot and immunohistochemistry (IHC) analyses further verified that this METTL3-MALAT1 axis activates the NF-κB pathway by modulating IκBα degradation and p65 nuclear translocation.
    CONCLUSIONS: Collectively, our work elucidates the METTL3-m6A-MALAT1-NF-κB regulatory axis in CRC, advancing the understanding of epigenetic mechanisms in cancer progression and providing a theoretical foundation for developing METTL3-targeted therapeutic strategies.
    Keywords:  Colorectal cancer; MALAT1; METTL3; NF-κB signaling pathway; m6A modification
    DOI:  https://doi.org/10.1186/s12967-026-08114-0
  32. Exp Neurol. 2026 Apr 29. pii: S0014-4886(26)00166-4. [Epub ahead of print] 115802
    Drugs targeting synaptic RNA m6A methylation regulate synaptic transmission and plasticity in the rat hippocampus.
    Rahaf Keskinen, Jun Kyu Rhee, Indrek Teino, Brunaldo Renzi, Mart Saarma, Sari E Lauri.
      m6A methylation is the most abundant modification in eukaryotic mRNA and has been implicated in epitranscriptomic regulation of various cellular functions. Recent studies have demonstrated its significance in brain development, neuronal signalling and memory formation; however, the precise mechanisms by which m6A RNA methylation affects synaptic transmission and plasticity in memory-related neuronal circuits remain unclear. Here, we have studied the effects of newly developed pharmacological compounds that target m6A methylation on excitatory synaptic transmission and plasticity in the hippocampus, using a combination of electrophysiological and immunohistological techniques in infant and adult rats. We demonstrate that STM2457, a highly potent catalytic inhibitor of the m6A methyltransferase METTL3, blocks long-term potentiation (LTP) without affecting basal synaptic transmission in area CA1. Moreover, our findings support that LTP in vivo is associated with elevated m6A immunostaining, suggesting that LTP induction triggers METTL3 activation and a subsequent rise in m6A methylation. Interestingly, pharmacological activation of METTL3/14 or inhibition of the m6A demethylase FTO increased synaptic m6A levels in vivo, yet attenuated LTP in adult hippocampal slices. METTL3/14 activation also diminished long-term depression (LTD). These findings align with a model where elevated m6A methylation acts as a stabilizing signal, limiting excessive activity-dependent plasticity of synaptic transmission across development. Furthermore, they add to the growing body of evidence supporting that dysregulation of m6A RNA methylation perturbs synaptic plasticity - the neurobiological foundation of memory - and demonstrate that these processes can be pharmacologically targeted.
    Keywords:  FTO; Hippocampus; METTL3/14; RNA m6A methylation; Synaptic plasticity; Synaptic transmission
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115802
  33. Mol Biol Cell. 2026 Apr 29. mbcE25100504
    Stage- and stress-specific phosphorylation of ribosomal protein Rps5 (uS7) by Smk1 and Kns1 kinases in Saccharomyces cerevisiae.
    Gwendolyn Resch, Thomas Swayne, Erica Johnson, Abhimannyu Rimal, Dimitri G Pestov, Natalia Shcherbik, Edward Winter.
      In the yeast Saccharomyces cerevisiae, nutrient deprivation triggers cell-type-specific responses: haploid cells exit the mitotic cycle and enter stationary phase, while diploid cells undergo meiosis and form spores. The meiosis-specific mitogen-activated protein kinase (MAPK) Smk1 regulates spore formation. The ubiquitously expressed Cdc2-like kinase (CLK) Kns1 downregulates ribosomal RNA and tRNA synthesis in mitotically dividing cells under nutrient-deprived conditions. Here, we show that Smk1 phosphorylates ribosomal protein Rps5 (uS7) on threonine residues 21 and 27 during the early stages of spore formation. As spore formation progresses, Kns1 is required to further increase the phosphorylation of these residues. Kns1-dependent phosphorylation of Rps5 is also observed in nutrient-deprived or rapamycin-treated haploid cells. Upon exposure to nutrient-rich media and spore germination, ribosomal subunits containing unphosphorylated Rps5 are incorporated into translationally active polysomes, while phosphorylated Rps5 is retained in inactive 80S ribosomes. Taken together, our data support a model in which Smk1 and Kns1 cooperate across the yeast life cycle to promote Rps5 phosphorylation and thereby bias a subset of ribosomes toward translational quiescence.
    DOI:  https://doi.org/10.1091/mbc.E25-10-0504
  34. Mol Cell Biochem. 2026 Apr 28.
    Co-translational profiling in the cardiac endothelium in response to LPS-induced inflammation in female mice in vivo: a proof-of-concept approach.
    Chad M Warren, Bhairavi Swaminathan, Paulina Langa, Stephanie R Villa, Walter C Thompson, Magdalena Chrzanowska, Jan K Kitajewski, R John Solaro, Beata M Wolska, Paul H Goldspink.
      Producing functional proteins involves multiple steps during mRNA translation on the ribosomes. However, co-translational regulatory mechanisms remain poorly characterized in intact mammalian systems. As a proof-of-concept, we developed a multi-omics approach to investigate endothelial-specific, co-translational regulation by modifying the translating ribosome affinity purification (TRAP) in vivo. We simultaneously co-immunoprecipitated (IP) polysome-associated mRNAs and proteins from the hearts of hemagglutinin-tagged ribosomal protein L22 mice (RiboTag) crossed with inducible endothelial-specific Cdh5CreERT2 mice (RiboTagEC). To perturb endothelial function, female mice were injected with E. coli lipopolysaccharide (LPS) (6 mg/Kg, i.p., 12 h). Hearts were homogenized, with ~ 10% used for input RNA-Seq and proteomics controls, and the remainder for IP of ribosome-bound polyadenylated mRNA and proteins. Endothelial cell transcripts (pecam1, cdh5) were enriched > 5-fold, while markers characteristic of other cell types were significantly depleted (< 0.05 q-value). We aligned transcriptomic and proteomic datasets (> 1250 overlapping terms) to identify pathways associated with concordant and discordant co-translational regulation. LPS was identified as the upstream regulator of the co-translational dataset that was concordantly regulated. Upregulated mRNAs but not proteins related to glycolysis were discordantly regulated. These findings validate our proof-of-concept multi-omics approach as a predictive platform for identifying disease-relevant pathways regulated at the co-translational level in vivo.
    Keywords:  Endothelium; Heart; Lipopolysaccharide; Ribosome; Translatome
    DOI:  https://doi.org/10.1007/s11010-026-05551-9
  35. FASEB Bioadv. 2026 Apr;8(4): e70108
    The Effects of Palmitoylethanolamide or Ibuprofen on the Abundance Profile and Synthesis Rate of Proteins in C2C12 Skeletal Myotubes.
    Paige L Cole, Connor A Stead, Jatin G Burniston, Daniel J Owens.
      Palmitoylethanolamide (PEA) and ibuprofen (IBU) exert anti-inflammatory effects that may influence skeletal muscle adaptation; however, their impact on muscle proteome dynamics remains unclear. Dynamic proteome profiling was performed in differentiated C2C12 myotubes treated for 36 h with D2O and either vehicle control (VC), PEA (10 μM), or IBU (100 μM). Protein-specific fractional synthesis rates (FSR; 1541 proteins) and relative protein abundances at 36 h (3085 proteins) were quantified and compared between treatments and VC. Relative to VC, PEA increased synthesis rates of 101 proteins (p < 0.05), whereas 2 proteins exhibited reduced synthesis. IBU increased synthesis rates of 165 proteins and reduced 7 proteins relative to VC. Both PEA and IBU increased total ribosomal protein synthesis (~80% relative to VC) and increased the abundance of 40S ribosomal subunit proteins (~18% relative to VC at 36 h). In addition, IBU treatment was associated with greater abundance of proteins involved in muscle contraction and extracellular matrix organization, reduced abundance of proteins associated with carbohydrate metabolism (21 proteins), and increased abundance of proteins linked to lipid metabolic pathways (17 proteins), relative to VC. In contrast, PEA-induced abundance differences were largely restricted to ribosomal proteins. These findings demonstrate that PEA and IBU enhance ribosomal protein turnover relative to control, whereas IBU elicits broader treatment-associated proteome remodeling.
    Keywords:  deuterium oxide; non‐steroidal anti‐inflammatory drugs; protein turnover; proteomics; skeletal muscle
    DOI:  https://doi.org/10.1096/fba.2025-00286
  36. Mediators Inflamm. 2026 ;2026(1): e4823996
    Evaluating Ribosomal Protein L19 mRNA as a Biomarker in Ulcerative Colitis: Implications for Severity Assessment.
    Lihao Shi, Guiyuan Jin, Xizhuang Gao, Yun Chen, Qian Zhao, Jian Lin, Guangxi Zhou.
       BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract, characterized by immune dysregulation, genetic susceptibility, and environmental factors such as diet and psychosocial stress. The etiology of UC is complex, involving multiple interrelated factors that drive its pathogenesis and clinical progression.
    METHODS: This cross-sectional study investigated the potential role of ribosomal protein L19 (RPL19) mRNA in UC. A total of 40 patients with UC and 29 healthy controls (HC) were prospectively enrolled from the Department of Gastroenterology, Affiliated Hospital of Jining Medical University, between November 2021 and November 2023. RPL19 mRNA levels in the intestinal mucosa of UC patients were quantified using quantitative PCR analysis. Subsequently, the associations of RPL19 mRNA expression with disease severity and with the levels of key inflammatory cytokines were statistically assessed.
    RESULTS: RPL19 mRNA expressions were significantly regulated in UC patients compared to HC. It exhibited a significant inverse correlation with the levels of both interleukin-2 (IL-2) and interleukin-4 (IL-4). Importantly, RPL19 mRNA levels also correlated with key clinical disease activity indices.
    CONCLUSIONS: This study demonstrates that mucosal RPL19 mRNA expression levels are significantly elevated in UC patients and correlate positively with endoscopic and histological disease severity. These findings identify RPL19 as a potential biomarker for reflecting local disease activity in UC.
    Keywords:  RPL19 mRNA; biomarkers; disease severity; inflammatory bowel disease (IBD)
    DOI:  https://doi.org/10.1155/mi/4823996
  37. Nucleic Acids Res. 2026 Apr 23. pii: gkag340. [Epub ahead of print]54(8):
    Structure of the hibernating Francisella tularensis ribosome and mechanistic insights into its inhibition by antibiotics.
    Martin Klima, Jan Silhan, Pavla Pavlik, Kamil Hercik, Evzen Boura.
      Francisella tularensis is the causative agent of tularemia, a zoonotic disease named after the Tulare County, California. Symptoms include sudden fever, chills, fatigue, and swollen lymph nodes, among others, and without treatment it is very serious or even fatal. In addition, F. tularensis is considered a potential bioterrorism threat due to its high infectivity and lethality. Ribosomes are key targets for many classes of antibiotics. In this study, we examined the F. tularensis ribosome and determined its structure at 2.5Å resolution using cryo-electron microscopy. Notably, we observed the stress-induced ribosome-associated inhibitor A (RaiA) protein bound to the ribosome. RaiA functions as a molecular hibernation factor, inhibiting bacterial translation in response to stress or nutrient deprivation. This mechanism parallels that described in the model organism Escherichia coli and in several pathogenic bacteria, such as Staphylococcus aureus. Furthermore, we solved structures of the antibiotics chloramphenicol and gentamicin bound to the F. tularensis ribosome. Collectively, these results provide structural insights that highlight previously unexplored opportunities for therapeutic intervention.
    DOI:  https://doi.org/10.1093/nar/gkag340
  38. Nucleic Acids Res. 2026 Apr 23. pii: gkag338. [Epub ahead of print]54(8):
    Systematic screening of archaeal MazF homologs reveals Tth-MazF1, a versatile, sequence-specific ribonuclease from Thermococcus thioreducens.
    Benjamin F Jepson, Eric J Wolf, Anthony R Dawson, Jingmin Jin, Vladimir Potapov, Nan Dai, Ivan R Corrêa, Erbay Yigit.
      Nucleotide- and sequence-specific ribonucleases are essential tools for dissecting RNA structure, modification, and composition, yet the enzymatic repertoire available for high-resolution RNA analysis remains limited. Here, we systematically screened 186 MazF homologs, including 164 from archaeal organisms, and identified 132 active endoribonucleases with diverse sequence preferences. Using a semi-high-throughput expression and purification workflow combined with an Illumina-based RNA-seq assay, we defined recognition motifs for 90 enzymes, uncovering a striking diversity of UG-rich cleavage specificities across the archaeal domain. Among these, Tth-MazF1, a thermostable endoribonuclease from the hyperthermophilic archaeon Thermococcus thioreducens, displayed robust and specific cleavage at U↓GN motifs across a broad range of temperatures (4°C-85°C). Tth-MazF1 enabled high sequence coverage of 0.8-8.9 kb messenger RNA (mRNA) transcripts by LC-MS/MS and direct detection of key structural features, including the 5' cap, poly(A) tail, and mass-altering epitranscriptomic modifications in ribosomal RNA. Tolerance of Tth-MazF1 to high temperatures, salt, and chemical modifications highlights it as a powerful enzymatic tool for analyzing chemically modified and structured RNAs. These findings position archaeal MazF proteins as a rich source of customizable RNases for biotechnology applications, such as mass spectrometry-based analysis of RNA-based vaccines and therapeutics as well as cellular RNAs.
    DOI:  https://doi.org/10.1093/nar/gkag338
  39. Front Cell Dev Biol. 2026 ;14 1788799
    Orchestrating innate immunity through RNA editing and helicase activity: ADAR1, dsRNA sensors, and tumor immune evasion.
    Moeko Minakuchi, Joseph M Salvino, Jessie Villanueva.
      Dysregulated dsRNA editing and RNA metabolism in cancer contribute to immune evasion, highlighting the critical role of RNA structural regulation in disease. Intracellular RNA structures regulate gene expression, innate immunity, genome stability, and cell fate. Among these, double-stranded RNA (dsRNA) is particularly important; exogenous dsRNA typically originates from viral infection, whereas endogenous dsRNA arises from repetitive elements or transcriptional errors, allowing cells to distinguish "self" from "non-self." The RNA-editing enzyme Adenosine Deaminase Acting on RNA 1 (ADAR1) prevents inappropriate innate immune activation by catalyzing adenosine-to-inosine (A-to-I) editing of endogenous dsRNA. RNA helicases complement this function by remodeling RNA structures and resolving nucleic acid hybrids, maintaining RNA homeostasis and immune surveillance. Recent studies have revealed an interplay between ADAR1 and RNA helicases that regulate dsRNA immunogenicity and R-loop dynamics, establishing this network as a key determinant of tumor immunity. Dysregulated RNA editing and structural regulation in cancer further underscore the potential of targeting these pathways therapeutically, providing strategies beyond conventional gene- or protein-centered approaches. In this review, we summarize current insights into how ADAR1 and RNA helicases control RNA structure, emphasize their roles in innate immune sensing, and discuss emerging approaches to modulate RNA editing and RNA architecture for therapeutic benefit. Taken together, research in this area positions RNA structural control as a central determinant of immune homeostasis and a promising frontier in cancer therapy.
    Keywords:  ADAR1; RNA editing; dsRNA sensors; helicase activity; tumor immune evasion
    DOI:  https://doi.org/10.3389/fcell.2026.1788799
  40. bioRxiv. 2026 Feb 07. pii: 2026.02.06.704297. [Epub ahead of print]
    Schlafen 11 (SLFN11) overexpression and nucleolar localization in response to bortezomib in multiple myeloma.
    Yasuhiro Arakawa, Daiki Taniyama, Kazuhito Suzuki, Shingo Yano, Yves Pommier.
      Proteins belonging to the Schlafen family are interferon-inducible and participate in the regulation of antiviral responses, immune signaling, and proteotoxic stress. SLFN11 kills cells with replicative damage, serving as a predictive biomarker for chemotherapeutic response. SLFN11 is epigenetically downregulated in ≈50% of solid tumors. Here we examined SLFN11 expression and significance in multiple myeloma (MM). Using TCGA and MMRF CoMMpass datasets, we find SLFN11 is consistently highly expressed across MM subtypes except CD1 and MAF/MAFB. CD138-positive normal and myeloma plasma cells retain SLFN11 expression even when proliferative activity (MKI67/Ki-67) increases with disease progression. SLFN11 expression strongly correlates with super-enhancer-driven plasma cell transcriptional programs. We report that bortezomib, a first-line MM treatment, induces SLFN11 accumulation in nucleoli with suppression of ribosomal RNA synthesis. SLFN11 knockout cells show enhanced bortezomib sensitivity and exatecan resistance, supporting SLFN11's protective role in proteotoxic stress and sensitizing role in replication stress. This study reveals that SLFN11 undergoes nucleolar translocation in response to proteasome inhibition in multiple myeloma, suppressing ribosomal RNA synthesis and conferring resistance to bortezomib while maintaining sensitivity to topoisomerase I inhibitors, thereby establishing SLFN11 as a dual-function biomarker for precision therapy selection in this disease.
    DOI:  https://doi.org/10.64898/2026.02.06.704297
  41. Biochemistry. 2026 Apr 30.
    How Medically Important Antimicrobials Bind to the 30S Ribosomal Subunit in a Bacterial Pathogen.
    Swati R Manjari, Caleb Mallery, Nilesh K Banavali.
      Ribosomes translate the genetic code in mRNA to synthesize proteins in all living organisms. Decoding of mRNA occurs in the small subunit of the ribosome and is mediated by tRNA anticodons. Regions near the decoding center are a target for antibiotics, such as aminoglycosides and tetracyclines, where their presence results in errors in protein synthesis. More than two decades of high-resolution structural studies have shown how such medically important antimicrobials (MIAs) bind to the small subunit of the bacterial ribosome. Here, we comprehensively analyze these previously reported structures to help understand the variability with which MIAs bind to small subunits of bacterial ribosomes. We previously solved the hibernating 70S ribosome structure of the bacterial pathogen Borrelia burgdorferi (Bbu), the causative agent of Lyme disease, but there is no structure of any MIA bound to this ribosome reported. Our structural analysis makes it possible to use inexpensive computational methods to predict the binding of these MIAs to the Bbu ribosomal 30S small subunit. For this, we used structural analogy, restrained energy minimization, and single-point binding free energy computations. We find the single-point binding free energy of the MIAs to be very sensitive to small conformational changes in the MIA and its environment. Incorporating this knowledge in structure-guided design could aid in the development of narrow-spectrum MIAs targeting specific bacterial pathogens.
    DOI:  https://doi.org/10.1021/acs.biochem.6c00008
  42. Oncol Lett. 2026 Jun;31(6): 254
    METTL5 reprograms glycolytic metabolism and promotes non-small cell lung cancer progression by modifying PGAM1.
    Yuchen Shan, Xiaoyu Duan, Kai Yuan, Ming Lou, Qiyong Wu, Zhaojia Gao.
      N6-methyladenosine (m6A) RNA methylation is implicated in cancer metabolism; however, to the best of our knowledge, the role of methyltransferase 5 (METTL5) in non-small cell lung cancer (NSCLC) progression remains unclear. Reprogrammed glycolytic metabolism (Warburg effect) supports tumor growth and immune evasion; however, the regulatory mechanisms of this process require further investigation. We hypothesized that METTL5 drives NSCLC progression by regulating glycolytic metabolism through m6A modification of phosphoglycerate mutase 1 (PGAM1) mRNA. The present study aimed to elucidate the molecular mechanisms, functional impacts and clinical relevance of the METTL5/PGAM1 axis. Integrated analyses of NSCLC cohorts from The Cancer Genome Atlas database were performed, and in vitro models (A549 and PC9 cell lines) and molecular techniques, including methylation inhibition, RNA stability assays and metabolic flux measurements (Seahorse XFe96 analyzer), were used. Key interactions were validated through western blotting, reverse transcription-quantitative PCR and correlation analyses. METTL5 was significantly upregulated in NSCLC tissues and in A549, PC9 and H520 cell lines, and high METTL5 expression was associated with poor patient survival (P<0.05). Silencing of METTL5 suppressed NSCLC cell proliferation and migration, while overexpression promoted proliferation and migration. METTL5 directly targeted PGAM1 mRNA through m6A modification, and the expression levels of METTL5 and PGAM1 exhibited a statistically significant but moderate positive correlation (R=0.45; P=5.4×10-56). YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) is an m6A reader that recognizes and binds to methylated PGAM1 mRNA, enhancing its stability and expression. PGAM1 knockdown reduced glycolysis (decreased extracellular acidification rate) and increased oxidative phosphorylation (increased oxygen consumption rate). Notably, the positive correlation between PGAM1 and GLUT1 expression (R=0.6; P=4.12×10-183) supports the role of the METTL5/PGAM1 axis in regulating GLUT1, thereby influencing glycolytic flux. Rescue experiments demonstrated that PGAM1 overexpression reversed GLUT1 downregulation in METTL5-knockdown cells. Overall, METTL5 may drive NSCLC progression by reprogramming glycolytic metabolism through m6A modification of PGAM1 mRNA. The METTL5/PGAM1/GLUT1 axis represents a novel therapeutic target for NSCLC.
    Keywords:  N6-methyladenosine RNA methylation; Warburg effect; glucose transporter type 1; methyltransferase 5; non-small cell lung cancer; phosphoglycerate mutase 1
    DOI:  https://doi.org/10.3892/ol.2026.15609
  43. bioRxiv. 2026 Apr 16. pii: 2026.04.15.718697. [Epub ahead of print]
    Structural basis of chaperone mechanisms in cells and the evolutionary emergence of the protein world.
    Ahhyun Son, Catherine Durso, Timothy A Whitehead, Scott Horowitz.
      How chaperones mediate protein folding in the crowded cell environment remains poorly understood. To gain insight, we developed CHAP-SEQ to examine how chaperones affect protein folding in cells at high throughput and amino acid resolution. Performing CHAP-SEQ using three chaperone proteins and one chaperone RNA reveals distinct modes of folding assistance. Chaperone proteins act preferentially on hydrophobic core residues, whereas chaperone RNA primarily targets structural or dynamic signatures. Furthermore, while the chaperone RNA has little preference for clients' baseline foldability, the chaperone proteins favor clients with greater intrinsic foldability. These differences are consistent with an evolutionary hypothesis in which greater chaperone complexity played a role in the formation of stable hydrophobic cores, suggesting a potential link between chaperone function and the evolution of protein folding.
    DOI:  https://doi.org/10.64898/2026.04.15.718697
  44. Biochem Mol Biol J. 2026 ;pii: 01. [Epub ahead of print]12(1):
    Evaluating the Effect of RNA Interference of Two Heat Shock Proteins (HSPA1L, HSP90B1) in Inducing Apoptosis in Acyrthosiphon Pisum.
    Griffin Davies, James Balthazor.
      Acyrthosiphon pisum (pea aphid) is a major pest of Fabaceae (legume) crops, causing direct feeding damage and transmitting plant diseases. Conventional control relies on broad-spectrum insecticides and natural enemies, both of which can harm non-target organisms and ecosystems. RNA interference (RNAi) offers a promising, species-specific alternative by silencing essential genes via double-stranded RNA (dsRNA). This study targeted two heat shock protein Genes-Heat Shock 70 kDa Protein 1-Like (HSPA1L) and Heat Shock Protein 90 kDa beta (Grp94) Member 1 (HSP90B1)-key players in protein folding, quality control, and stress response within the Unfolded Protein Response (UPR) pathway. These chaperones stabilize proteins, assist in folding newly synthesized polypeptides, and target misfolded proteins for degradation. Silencing these genes was hypothesized to cause accumulation of misfolded proteins, triggering Endoplasmic Reticulum (ER) stress, UPR overload, and ultimately apoptosis, leading to aphid mortality. Total RNA was extracted from adult pea aphids, reverse-transcribed to cDNA, and used to synthesize gene-specific dsRNAs for HSPA1L and HSP90B1. These dsRNAs were encapsulated in Branched-Amphiphilic Peptide Capsules (BAPCs) and delivered orally at concentrations of 10 ng/μL and 100 ng/μL via artificial diet feeding. Survival was monitored every 6 hours for 48 hours on dsRNA diet, followed by transfer to healthy faba bean leaves. Preliminary studies indicated positive correlations between gene knockdown and elevated mortality. Results demonstrated significantly reduced survival in treated groups compared to controls at both concentrations (Kaplan-Meier survival analysis, log-rank p<0.001), supporting the induction of apoptosis. This approach highlights the potential of UPR-targeted RNAi for eco-friendly, targeted pest control.
    Keywords:  Aphid; Knockdown; Pest mitigation; RNAi; Silencing; Unfolded protein response; dsRNA
  45. J Cell Biol. 2026 Jun 01. pii: e202601119. [Epub ahead of print]225(6):
    The environmental stress response regulates biophysics of the cytoplasm and survival in quiescence.
    Lorena Kronig, Carmen A Weber, Pablo Aurelio Gómez-García, Jonas S Fischer, Christian Doerig, Agnès Michel, Paolo Ronchi, Sarah Khawaja, Paola Picotti, Benoît Kornmann, Karsten Weis.
      All organisms employ strategies to cope with changing environmental conditions. In budding yeast, nutrient deprivation induces a reversible non-proliferative state known as quiescence, characterized by extensive remodeling of gene expression, metabolism, and cellular biophysical properties. Yeast cells survive prolonged periods of starvation-induced quiescence, provided they can respire in the early stages of glucose withdrawal, and blocking respiration causes premature aging and markedly reduced survival and cytoplasmic diffusion. We find that respiration is required to initiate a quiescence-specific adaptive program. Induction of such a program prior to glucose withdrawal bypasses the need for respiration, rescuing survival and biophysical properties to the levels of respiration-competent cells. This rescue relies on proteomic adaptation and is mediated by Ras/PKA inactivation and Msn2/4-dependent activation of the environmental stress response, leading to modulation of cytoplasmic diffusion. Together, this enables long-term survival in quiescence even in the absence of respiration, underscoring the role of the stress response and the modulation of cytoplasmic properties in quiescence and aging.
    DOI:  https://doi.org/10.1083/jcb.202601119
  46. BMC Biol. 2026 Apr 29.
    HNRM: hyperedge neighborhood-based representation for predicting N6-methyladenosine-related regulatory pathways.
    Dongdong Jiang, Yan Li, Liang Yu.
       BACKGROUND: N6-methyladenosine (m6A), the most predominant post-transcriptional RNA modification, regulates splicing, translation, and decay processes. Its dysregulation is implicated in cancers, metabolic disorders, and neurological diseases. Despite accumulating evidence highlighting m6A as a key player in human pathologies, no previous computational framework has investigated the high-order associations among m6A sites, diseases, and drugs within a unified model.
    RESULTS: Here, we introduce HNRM, a data-driven approach designed to model hyperedges across these entities. We frame this problem as a high-order link-prediction task on a hypergraph. We employ a hypergraph neural network based on hyperedge neighborhoods to learn embedding representations of both hyperedges and nodes.
    CONCLUSIONS: The performance of HNRM is evaluated on a newly collected and processed m6A dataset, as well as on five additional datasets from other domains, demonstrating its superior effectiveness. Ablation studies and Gene Ontology enrichment analysis further validate its capability in identifying potential associations.
    Keywords:  Hyperedge neighborhood; Hypergraph representation learning; RNA N6-methyladenosine
    DOI:  https://doi.org/10.1186/s12915-026-02612-9
  47. Protein Sci. 2026 May;35(5): e70585
    Quality control of protein import into mammalian mitochondria.
    Madeleine Goldstein, Laurie Lee-Glover, Hilla Weidberg.
      Mitochondrial function depends on the continuous import of hundreds of nuclear-encoded proteins. Targeting and translocation of mitochondrial proteins is a multistep process that is inherently vulnerable to defects in cytosolic quality control systems as well as perturbations in mitochondrial protein import machinery and organelle function. Failure of mitochondrial protein import has dual consequences: it compromises mitochondrial biogenesis and activity, and it poses a cytosolic proteotoxic threat due to the accumulation of unimported precursor proteins. Accordingly, mitochondrial protein import defects are detrimental to cellular homeostasis and are associated with a wide range of disorders, including metabolic and neurodegenerative diseases. Cells therefore rely on layered quality control systems that monitor mitochondrial protein biogenesis and mitigate stress arising from mislocalized mitochondrial proteins. In this review, we summarize recent progress in understanding pathways that modulate mitochondrial protein import and the fate of unimported proteins in mammals. We highlight cytosolic and mitochondrial protein quality control mechanisms and discuss how import defects are translated into cellular stress responses and mitochondrial protective programs to restore cellular and mitochondrial homeostasis.
    Keywords:  Proteostasis; mitochondrial dysfunction; mitochondrial protein import; quality control mechanisms; stress responses
    DOI:  https://doi.org/10.1002/pro.70585
  48. JACS Au. 2026 Apr 27. 6(4): 2161-2175
    Advantages and Challenges of G‑Quadruplexes in Regulating Alternative Splicing.
    Haiyan Huang, Xiang Zhou.
      Alternative splicing (AS) is a fundamental process that dramatically expands the proteomic diversity of eukaryotes. The precise regulation of AS is governed by the complex interplay between cis-regulatory elements in the pre-mRNA and trans-acting protein factors. Recently, RNA secondary structures have emerged as critical players in the regulatory landscape. Among these, G-quadruplexes (G4s), which are stable four-stranded structures formed by guanine-rich (G-rich) sequences, have been identified as potent regulators of splicing outcomes. This review synthesizes the current understanding of the role of RNA G4s in AS, focusing on three interconnected pillars: (1) the characteristic sequence features and genomic distribution of G4-forming motifs near splice sites revealing a significant strand-specific enrichment that suggests a conserved regulatory function; (2) the multifaceted interactions between G4 structures and RNA-binding proteins which can act as splicing enhancers or repressors by binding to single-stranded G-tracts or structured G4s; and (3) the profound impact of G4-stabilizing or -destabilizing small molecules, which can be harnessed to deliberately re-engineer splicing patterns in genes linked to cancer, neurodegeneration, and other diseases. By integrating findings from genomic analyses, biochemical studies, and chemical biology approaches, this review aims to expound G4 structures as dynamic, druggable nodes in the splicing regulatory network, offering novel mechanistic insights and promising therapeutic avenues.
    Keywords:  G4 ligands; G4-related proteins; alternative splicing; g-quadruplex
    DOI:  https://doi.org/10.1021/jacsau.6c00168
  49. Int J Nanomedicine. 2026 ;21 590745
    Research on the Inhibition of Cancer Cell Metastasis by Graphene Oxide Suppresses the Translation of the Snail mRNA.
    Xinyu Wei, Can Luo, Xiaohong Ming, Xianbo Jia, Ping Long, Lei Feng, Ming Zhu, Xiaolin Hu, Ming Li, Hui Li.
       Introduction: Lung cancer is the most common malignant tumor worldwide and often presents with advanced metastasis. This study explores the effects of graphene oxide (GO) on lung cancer cell motility, investigates underlying mechanisms, and identifies potential therapeutic targets.
    Methods: The effects of GO on the viability and motility of lung cancer cells A549 and H226, and normal bronchial epithelial cells BEAS-2B, were assessed using cytotoxicity, scratch, and Transwell assays. Mechanisms were explored by measuring intracellular ROS, EMT-related and TGF-β pathway protein expression, cellular TGF-β release, and Snail mRNA levels, suggesting potential new targets.
    Results: Cytotoxicity, scratch, and Transwell experiments indicated that GO had cytotoxic effects on A549, H226, and BEAS-2B, and the effects increased with increasing GO concentration and culture time. A specific concentration of GO could significantly inhibit the cell motility of A549 and H226 within a specific time window. The results of the molecular mechanism experiment showed that within the selected GO concentration and time window, there was no significant change in intracellular reactive oxygen species (ROS); the epithelial-associated protein E-cadherin increased, the EMT regulatory protein Snail decreased, the level of TGF-β secreted by cells did not change, and the expression level of Snail mRNA increased.
    Conclusion: GO increases Snail mRNA but suppresses its translation, reducing EMT protein Snail and increasing E-cadherin, which further decreases tumor cell motility, offering a novel therapeutic strategy for addressing distant metastasis in lung cancer.
    Keywords:  Snail mRNA; epithelial-mesenchymal transition; graphene oxide; metastasis of lung cancer cells; protein synthesis
    DOI:  https://doi.org/10.2147/IJN.S590745
  50. Genes Dev. 2026 Apr 27.
    DDX3X-mediated translation of structured cardiac mRNAs is essential for female heart development.
    Kayla K Mason, Seohyun K Park, James I Emerson, Yao Wei Lu, Da-Zhi Wang, William F Marzluff, Frank L Conlon.
      Sex differences influence congenital heart disease (CHD) development, yet underlying molecular mechanisms remain largely unclear. We demonstrate that the X-linked RNA helicase DDX3X associates in the heart with ribosomal subunit proteins, and eCLIP mapping reveals its preferential binding to cardiac mRNAs with long, structured 5' untranslated regions (UTRs) that can hinder translation. Using a cardiomyocyte-specific mouse Ddx3x knockout model, we show that female embryos lacking Ddx3x die at midgestation from heart failure due to impaired translation of key cardiac regulators, whereas male littermates survive. Ribosome profiling and proteomics demonstrate that DDX3X is required for efficient translation of female differential cardiac mRNAs. Reporter assays confirm that translation of essential cardiac genes such as Srf and Rcor2 depends on their 5' UTRs and requires DDX3X. These findings uncover a sex-specific posttranscriptional mechanism by which DDX3X safeguards female heart development through selective mRNA translation, providing insight into how X-linked dosage-sensitive regulators contribute to CHD.
    Keywords:  DDX3X; cardiac; heart; posttranscription; sex differences; translation
    DOI:  https://doi.org/10.1101/gad.353320.125
  51. Mar Drugs. 2026 Apr 15. pii: 138. [Epub ahead of print]24(4):
    Marine Bioactives in Liver Aging: Mechanistic Insights and Translational Potential.
    Ricardo Moreno Traspas, Zachariah Tman.
      The liver is a central regulator of systemic metabolism and exhibits exceptional regenerative capacity, yet aging progressively impairs hepatic resilience through metabolic dysregulation, mitochondrial dysfunction, epigenetic instability, and chronic inflammation. Marine ecosystems constitute a vast and underexplored source of structurally diverse bioactive compounds that have evolved to modulate conserved stress response and homeostatic pathways. This review synthesizes current preclinical evidence demonstrating how marine-derived metabolites target key molecular axes implicated in liver aging, including energy sensing, redox balance, mitochondrial quality control, inflammatory signaling, and chromatin-associated regulation. Rather than focusing solely on isolated hepatoprotective effects, we frame marine bioactives within an aging biology perspective, highlighting their ability to modulate pathways associated with cellular plasticity and resilience. We further propose that this mechanistic convergence provides a theoretical framework for exploring marine compounds as potential adjunctive modulators within emerging, experimental liver rejuvenation strategies, including partial cellular reprogramming approaches that require coordinated metabolic and epigenetic control. While acknowledging that direct reversal of liver aging remains to be clinically established, integrating marine chemodiversity with contemporary aging and regenerative biology outlines a conceptual roadmap for developing liver-directed interventions targeting aging-related vulnerability as a fundamental driver of disease.
    Keywords:  aging; epigenetics; liver; marine bioactives; metabolic dysfunction; oxidative stress; rejuvenation; senescence
    DOI:  https://doi.org/10.3390/md24040138
  52. PLoS Biol. 2026 Apr 27. 24(4): e3003775
    Polyphosphate modulates the stress-responsive formation of functional RNA-protein condensates in bacteria and mammalian cells.
    Jian Guan, Rebecca Lee Hurto, Akash Rai, Janakraj Bhattrai, Christopher A Azaldegui, Luis A Ortiz-Rodríguez, Quancheng Liu, Julie S Biteen, Lydia Freddolino, Ursula Jakob.
      Uncovering what drives select biomolecules to form phase-separated condensates in vivo and identifying their physiological significance are topics of fundamental importance. Here, we show that nitrogen-starved Escherichia coli produces long-chain polyphosphates, which scaffold the RNA chaperone Hfq into high molecular weight complexes, which eventually phase separate together with components of the RNA translation and processing machinery. The presence of polyphosphate within these condensates controls Hfq function by selectively stabilizing polyadenylated RNAs involved in transcription and protein translation and by promoting interactions with translation- and RNA-metabolism-associated proteins involved in de novo protein synthesis. Lack of polyphosphate significantly impairs condensate formation, increases cell death, and hinders recovery from N-starvation. In functional analogy, we demonstrate that polyP contributes specifically to the formation of Processing (P)-bodies in human cell lines, revealing that a single, highly conserved and ancestral polyanion serves as a modulator for functional phase-separated condensate formation across the tree of life.
    DOI:  https://doi.org/10.1371/journal.pbio.3003775
  53. Trends Biotechnol. 2026 Apr 30. pii: S0167-7799(26)00140-X. [Epub ahead of print]
    RNA sensors and actuators for dynamic cellular regulation.
    Anthony M Stohr, Helena Hansen, Derron Ma, Mark Blenner, Wilfred Chen.
      RNA naturally regulates many cellular processes, yet the engineering of RNA for use in synthetic cellular control schemes lags behind protein-based systems. Recent advancements in synthetic biology, investment in RNA therapeutics, and a better understanding of RNA structural dynamics have driven the development of novel RNA sensors and actuators. The genetic information encoded within RNA enables facile sensing and interactions with other nucleic acids, while its dynamic structure facilitates binding to a broad array of small-molecule and protein ligands. RNA can be engineered to sense these diverse inputs and transduce signals to regulate cellular activity on the transcriptional, translational, and post-translational levels to enhance microbial biosynthesis and create targeted gene therapies.
    Keywords:  RNA biosensors; RNA editing; RNA engineering; aptamers; dynamic regulation; synthetic biology
    DOI:  https://doi.org/10.1016/j.tibtech.2026.04.005
  54. Virol J. 2026 Apr 28.
    Therapeutic modulation of HIV-1 using miRNAs and lncRNAs: from bench to bedside.
    Akmal Zubair, Nguyen Manh Hung, Yasir Waheed, Naila Afghan.
      Long non-coding RNAs, often referred to as lncRNAs, consist of RNA molecules that contain more than 200 nt and can be translated into small proteins under various circumstances. Extensive research has consistently demonstrated that long non-coding RNAs (lncRNAs) and miRNAs play a crucial role in various biological processes and disease mechanisms, including those associated with viral infections. Although numerous mechanisms are involved in miRNA and lncRNA-mediated gene regulation, such as transcriptional and translational regulation, protein modification, and the formation of RNA-protein complexes. This manuscript demonstrates the new therapeutic roles of long ncRNA (lncRNA) and microRNA (miRNA) in the treatment of HIV-1 infection. It shows that these non-coding RNAs have decisive roles in controlling the viral replication, latency, and host-virus interactions in the epigenetic, transcriptional and post-transcriptional processes. Select lncRNAs like MALAT1, NEAT1, NRON, and GAS5 are demonstrated to increase or block HIV transcription and persistence, whereas miRNAs like miRNA-155, miRNA-146a and miRNA-191- 5p regulate immune reactions and viral replication by acting on both viral RNA and host dynamics. The article also highlights that certain disadvantage of lncRNA such as delivery efficiency, stability of RNA therapeutics, potential off-target effects, and the difficulty of targeting HIV reservoirs.
    Keywords:  AIDS; HIV; LncRNAs; MiRNAs; Therapy
    DOI:  https://doi.org/10.1186/s12985-026-03175-5
  55. Cell Stem Cell. 2026 Apr 30. pii: S1934-5909(26)00146-3. [Epub ahead of print]
    eIF4G2-mediated selective translation of chromatin regulators safeguards adult intestinal stem cell identity and differentiation.
    Haruko Kunitomi, Aye Myat Khaine, Radia Jamee, Vanessa Arreola, Mariselle Lancero, Amba Raychaudhuri, Samuel Perli, Yoshiko Sato, Mio Iwasaki, Pedro Ruivo, Kiichiro Tomoda, Mari Mito, Yuichi Shichino, Shintaro Iwasaki, Shinya Yamanaka.
      eIF4G2 (DAP5/NAT1) is a non-canonical translation initiation factor, but its role in homeostasis is unclear. Using inducible Eif4g2 knockout mice and intestinal organoids, we show that eIF4G2 loss collapses Lgr5+ intestinal stem cell (ISC) and secretory maturation programs while preserving villus architecture. Transcriptomic and single-nucleus multiome analyses reveal a durable fetal-like/regenerative state with YAP-TEAD activation and regenerative absorptive cells. Ribosome profiling identifies selective translation-efficiency loss among chromatin regulators, especially the KAT3 coactivators CREBBP and EP300, resulting in reduced KAT3 abundance and global histone acetylation; chemical KAT3 inhibition phenocopies this state. CUT&Tag and assay for transposase-accessible chromatin sequencing (ATAC-seq) demonstrate that reduced eIF4G2-KAT3 output drives locus-selective enhancer remodeling, with loss of adult ISC/Wnt-Notch elements and activation of TEAD-enriched fetal loci, without inflammatory or integrated stress response programs driving the transition. Fetal intestinal spheroids remain viable despite similar biochemical defects, highlighting a stage-specific requirement for translational buffering in maintaining adult identity.
    Keywords:  differentiation; eIF4G2 (NAT1/p97/DAP5); epigenetic gene regulation; histone modification; intestinal stem cell; translation initiation
    DOI:  https://doi.org/10.1016/j.stem.2026.04.006
  56. Nucleic Acids Res. 2026 Apr 23. pii: gkag352. [Epub ahead of print]54(8):
    How interdiction of inositol pyrophosphate catabolism perturbs the fission yeast response to phosphate starvation.
    Jill Babor, Ana M Sanchez, Isabel Prucker, Henning J Jessen, Beate Schwer, Stewart Shuman.
      In fission yeast, inositol-1-pyrophosphates drive the synthesis of vacuolar inorganic polyphosphate (polyP), which serves as a phosphate reservoir during nutrient scarcity. Acute phosphate starvation of wild-type fission yeast cells triggers rapid depletion in tandem of inositol-1-pyrophosphates and polyP, and a gradual transition to G0 quiescence. Here, we report that HASX yeast cells, which lack the three pyrophosphatase enzymes that catabolize inositol pyrophosphates, mount an aberrant response to phosphate starvation associated with sustained elevation of inositol-1-pyrophosphates. This entails immediate cessation of growth; precocious onset of the phosphate starvation transcriptional program; persistently high vacuolar polyP levels; and rapid loss of polysomes, accumulation of 80S monosomes, and inefficient translation of starvation-induced pho1 mRNA. Two key findings are that: (i) the deviant phosphate starvation phenotype in HASX cells is effaced by deletion of vacuolar polyP polymerase Vtc4; and (ii) overdrive of Vtc4-catalyzed polyP synthesis by excess inositol-1-pyrophosphates rapidly exhausts the GTP pool in phosphate-starved HASX cells. GTP depletion, together with precocious repression of genes encoding translation factor GTPases, is the likely cause of the polysome decay. Our results provide new insights into how inositol pyrophosphate signaling and polyP dynamics influence the translation machinery, phosphate homeostasis, and the transcriptional response to nutrient stress.
    DOI:  https://doi.org/10.1093/nar/gkag352
  57. Annu Rev Biomed Data Sci. 2026 Apr 28.
    Mechanistic Mutational Scanning to Uncover the Secret Life of Proteins.
    Matthew K Howard, Willow Coyote-Maestas.
      Deep mutational scanning (DMS) has emerged as a transformative tool for dissecting individual protein function and broader cell biology. DMS methods enable comprehensive interrogation of sequence-function relationships by systematically testing thousands of genetic variants within a pool for their effect(s) on diverse phenotypes. This review focuses on how these approaches are revolutionizing mechanistic protein biology, cell biology, and pharmacological research. We present a conceptual framework to organize genetic perturbations with phenotypic readouts along a nested cellular continuum-from protein folding and biogenesis to trafficking, posttranslational modification, protein-protein interactions, and downstream signaling. We highlight recent advances in mapping allosteric networks, pharmacologic mechanisms, and multiphenotype screening technologies. These mechanistic insights are reshaping our understanding of protein function at the residue level and informing our understanding of drug action, allostery, the interpretation of rare variants, and protein engineering strategies.
    DOI:  https://doi.org/10.1146/annurev-biodatasci-092624-104436
  58. Cancer Biol Ther. 2026 Dec 31. 27(1): 2664967
    IGF2BP3 promotes gastric cancer progression by inhibiting ferroptosis through ETV4-mediated regulation of GCH1.
    Kan Li, Hui Wei, Fang Li, Ya Zheng, Yongning Zhou.
       BACKGROUND: Ferroptosis can be inhibited by insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) in cancers. ETS variant transcription factor 4 (ETV4) is aberrantly expressed in various cancers. Elevated transcription of guanosine triphosphate cyclohydrolase 1 (GCH1) contributes to tumor malignancy. This study investigated the involvement of IGF2BP3, ETV4, and GCH1 in ferroptosis in gastric cancer (GC).
    METHODS: GC cells and tissue samples were used to detect IGF2BP3, ETV4, and GCH1 expression. The relationships between IGF2BP3, ETV4, and GCH1 were assessed using RNA immunoprecipitation assay, chromatin immunoprecipitation assay, and dual-luciferase reporter assay. BALB/c nude mice were utilized to establish GC tumor xenografts. Cell cloning and Transwell were used to detect the proliferation, migration, and invasion of cells.
    RESULTS: IGF2BP3 and ETV4 were upregulated in GC. IGF2BP3 regulated ETV4 protein level by mediating its mRNA stability. Knockdown of ETV4 inhibited GC cell proliferation, migration, and invasion, and promoted their ferroptosis. ETV4 also promoted the transcription of GCH1 by directly binding to its promoter region. GCH1 overexpression diminished the facilitating effect of ETV4 knockdown on ferroptosis in GC. Overexpression of GCH1 also eliminated the promoting impact of IGF2BP3 knockdown on GC cell proliferation, migration, and invasion. Lastly, inhibition of GCH1 reversed the promoting effect of IGF2BP3 overexpression on GC tumor growth in vivo.
    CONCLUSIONS: IGF2BP3 promotes tumor growth and inhibits ferroptosis in GC by regulating ETV4, while ETV4 promotes GCH1 expression by direct interaction with its promoter. GCH1 overexpression counteracts the effects of ETV4 and IGF2BP3 on GC.
    Keywords:  ETV4; GCH1; IGF2BP3; ferroptosis; gastric cancer
    DOI:  https://doi.org/10.1080/15384047.2026.2664967
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