bims-spribo 2026-11-01 papers

bims-spribo

Biomed News

on Specialized ribosomes

Issue of 2026–11–01
27 papers selected by
Maxim Bouvet, Università di Torino

Ribosome structure, function and dysfunction at the molecular level.
A small modification makes a big difference: rRNA modifications in hematopoiesis and leukemia.
Autonomous Biogenesis of Early and Late Assembly Intermediates of a Large Ribosomal Subunit in a Minimal System.
Using All Probes Plasmids to Lower the Barrier for Quantifying Single-mRNA Translation Dynamics in Live Cells.
Endogenous targets of Zuo1-mediated mRNA surveillance encode proteins with higher predicted disorder.
E. coli RsmF activity depends on prior modification of 16S rRNA helix 44.
RNA recognition and cleavage in archaeal ribosome biogenesis: insights from FAU-1.
Nuclear respiratory factor 1 supports NPM1 expression and contributes to the regulation of a subset of ribosome biogenesis genes.
Molecular sterics guide tmRNA translocation on the ribosome.
Defective Ribosome Biogenesis Drives Tubular Senescence and Renal Fibrosis via IRBC-p53 Activation.
Dynamic phosphorylation of TCOF1 controlled by CK2 and PPM1D regulates nucleolar condensation and RNA polymerase I activity.
RSV competes with the host for translational machinery without a host shutoff strategy.
CSE1L enrichment in pediatric and young adult acute myeloid leukemia reveals a ribosomal export dependency.
EWSR1 associates with the 40S ribosomal subunit and represses translation to maintain endoplasmic reticulum homeostasis.
Ribosomal proteins are major substrates of starvation-induced endosomal microautophagy in Drosophila.
Arginine rewires eIF4F translation initiation to overcome fever-induced CAR T cell dysfunction.
RiboFlow v2: a configurable ribosome profiling pipeline reveals measurements sensitive to read-mapping methodology.
Antimicrobial peptides derived from Nemuri induce ribosomal condensation to inhibit translation.
KDM3B regulates hair follicle stem cell differentiation by activating the mTOR-dependent translation program.
Structural probing of RNA hairpins quantifies protein occupancy on RNA and links it to function in human cells.
m⁶A presence and dosage are associated with IGF2BP2 binding, RNA abundance, and translation in mouse heart and liver.
Methylated eEF1A selectively decodes mRNA to shape cancer proteomes.
ALS-linked FUS mutation impairs GEMIN5-dependent mRNA recruitment to neuronal late endosomes.
Role of Leu and Val synthesis in sensing mitochondrial nutrient and energy availability.
Cryo-EM and biochemical characterization of a BRAF/CRAF heterodimer shows that the NtA motif negative charge is dispensable for RAF activation.
Pharmacological inhibition of METTL1 as a therapy against solid and blood cancers.
The nonsense-mediated decay RNA-surveillance pathway facilitates the hypoxia response by C. elegans.

Semin Hematol. 2026 Oct 03. pii: S0037-1963(26)00091-0. [Epub ahead of print]

Ribosome structure, function and dysfunction at the molecular level.

Ruta Chitale, Arlen W Johnson.

  Ribosomes are essential ribonucleoprotein complexes that translate genetic information into proteins and are therefore central to cellular growth, development, and homeostasis. Recent advances in structural biology and genomics have transformed our understanding of ribosomes from static translational machines to highly dynamic complexes whose assembly, function, and quality control are tightly regulated. In this review, we provide an overview of eukaryotic ribosome structure and biogenesis, focusing on insights gained from yeast and human systems. We discuss the hierarchical assembly of ribosomal subunits, rRNA processing and modification, nuclear export, and cytoplasmic maturation. Particular emphasis is placed on the surveillance mechanisms that monitor ribosome assembly, including structural proofreading, molecular mimicry, RNA decay pathways, and translation-like "test-drive" reactions that assess ribosome competence. We further examine how defects in ribosome biogenesis and translation activate nucleolar surveillance, ribosome quality-control pathways, and downstream stress-response networks, including p53 signaling, the integrated stress response, and ribotoxic stress pathways. Together, these mechanisms form an interconnected quality-control system that safeguards ribosome function and cellular protein homeostasis. These studies provide important insights into the molecular basis of numerous ribosomal diseases and related disorders associated with defective ribosome biogenesis and function. Finally, we highlight emerging questions regarding ribosome heterogeneity, specialization, and the relationship between ribosome quality control and human disease.

Keywords:  Quality control; Ribosome; Ribosome assembly; Ribotoxic stress

DOI:  https://doi.org/10.1053/j.seminhematol.2026.09.011
Semin Hematol. 2026 Oct 01. pii: S0037-1963(26)00095-8. [Epub ahead of print]

A small modification makes a big difference: rRNA modifications in hematopoiesis and leukemia.

Neta Ifergan, Sivan Ben Dror, Daphna Nachmani.

  Hematopoietic stem cells (HSCs) sustain lifelong blood production through a fine balance between self-renewal and differentiation that demands a tight regulation of protein synthesis. HSCs are highly sensitive to translational perturbation, as exemplified by human ribosomopathies-a group of congenital bone marrow failure syndromes caused by mutations in ribosomal components and biogenesis factors. While the contribution of ribosome numbers to hematologic disease is established, ribosome composition is emerging as an equally important axis of regulation. A central source of this compositional diversity is ribosomal RNA (rRNA) nucleotide modifications-human rRNAs carry over 200 chemical modifications, primarily 2'-O-methylation and pseudouridylation, which were long regarded as static structural features but are now recognized as dynamically regulated during cellular differentiation. Perturbation of these modification patterns has profound consequences. In dyskeratosis congenita, germline mutations to rRNA modification-related proteins disrupt rRNA modifications landscape, and cause bone marrow failure through selective translational defects without globally compromising ribosomes numbers. Conversely, in acute myeloid leukemia, leukemic stem cells actively maintain high rRNA modification levels at specific sites to sustain self-renewal, metabolic fitness, and chemoresistance, effectively driving a stem-like translational state. In this review, we integrate findings from normal hematopoietic differentiation, congenital bone marrow failure syndromes, and leukemia to describe how rRNA modifications link translation to cell fate in the hematopoietic system. We discuss the dynamics of rRNA modifications as determinants of cellular identity and highlight emerging therapeutic opportunities, as well as the significant gaps that remain in this expanding field.

Keywords:  Hematopoiesis; Hematopoietic stem cells; Leukemia; Ribosomes; rRNA modifications

DOI:  https://doi.org/10.1053/j.seminhematol.2026.09.008
J Am Chem Soc. 2026 Oct 28. 148(42): 45830-45839

Autonomous Biogenesis of Early and Late Assembly Intermediates of a Large Ribosomal Subunit in a Minimal System.

Noa Avidan, Michael Levy, Yuval Oren, Yoshihiro Shimizu, Roy H Bar-Ziv, Shirley S Daube.

Cell-free autonomous biogenesis of ribosomes is important for the bottom-up assembly of an artificial cell and for engineering of functional ribosomes with novel activities. The challenge lies in establishing conditions for a single-step multicomponent synthesis and assembly process in a minimal transcription-translation reaction. We previously reported autonomous synthesis and assembly of a bacterial small ribosomal subunit, but the assembly pathway of the large subunit is more complex with dozens of proteins that bind, fold, and chemically modify its ∼3000-base-long rRNA (rRNA). Here, we cosynthesized all the large subunit components including 33 ribosomal proteins (r-proteins) and 2 rRNAs from DNA brushes and followed the dynamics of assembly coupled to synthesis in real time using total internal reflection fluorescence microscopy. A systematic screen of the binding of each of the ribosomal proteins to the 23S rRNA revealed an assembly pattern indicative of early intermediates. The addition of genes coding for six rRNA assembly factors facilitated binding of late assembly ribosomal proteins, supporting formation of late-stage intermediates even in the absence of rRNA modifications. We established a scenario for the large subunit biogenesis via macromolecular colocalization that may aid in the identification and characterization of additional genes required for achieving complete functional ribosome self-regeneration in a minimal system.

DOI: https://doi.org/10.1021/jacs.6c13587
Methods Mol Biol. 2027 ;3101 89-103

Using All Probes Plasmids to Lower the Barrier for Quantifying Single-mRNA Translation Dynamics in Live Cells.

Sam Klink, Gabriel Galindo, Timothy J Stasevich.

  Translation of mRNA into full-length protein is a relatively short-lived and dynamic process. Many classical biochemical techniques lack the resolution required to capture both spatial and temporal information of ribosome activity-initiation, elongation, and termination. This limitation is exacerbated in a live cell context. Recent advances in plasmid expression vectors, epitope tags, and fluorescent proteins now allow for quantitative and stream-lined imaging of single-mRNA translation in living cells. This protocol describes the use of "All Probes Plasmids" to lower the barrier for imaging and quantifying single-mRNA translation events in living cells.

Keywords:  Fluorescence microscopy; Live-cell imaging; Ribosomal dynamics; Single-molecule; mRNA translation

DOI:  https://doi.org/10.1007/978-1-0716-5687-7_5
iScience. 2026 Nov 20. 29(11): 117945

Endogenous targets of Zuo1-mediated mRNA surveillance encode proteins with higher predicted disorder.

Suhee Chang, Jeff Coller.

  Zuo1 slows elongating ribosomes in response to nascent peptide misfolding, which in turn triggers co-translational decay of the transcript. The endogenous substrates of this pathway have remained undefined. Using RNA-sequencing and ribosome profiling of unstressed wild-type and zuo1Δ cells, we identified transcripts that accumulate in the absence of Zuo1, representing mRNAs normally downregulated by Zuo1-mediated surveillance. Proteins encoded by these transcripts displayed higher predicted disorder across multiple metrics, were enriched in basic residues, were depleted of proline residues, and were shorter in length. Ribosome profiling revealed that Zuo1 target transcripts exhibited higher ribosome occupancy in the presence of Zuo1, and the ratio of wild-type to zuo1Δ ribosome occupancy positively correlated with predicted disorder. These findings indicate that Zuo1 surveillance acts preferentially on transcripts encoding nascent chains that fail to acquire stable structure.

Keywords:  Zuo1; disordered proteins; mRNA decay; protein misfolding; ribosome speed; translation elongation

DOI:  https://doi.org/10.1016/j.isci.2026.117945
Nucleic Acids Res. 2026 Oct 24. pii: gkag1005. [Epub ahead of print]54(20):

E. coli RsmF activity depends on prior modification of 16S rRNA helix 44.

Mohamed I Barmada, Aya Hanna, Camden R Bair, Erin N McGinity, Natalia Zelinskaya, Debayan Dey, Graeme L Conn.

Bacterial ribosomal RNA (rRNA) methylations are important for accurate translation. Four distinct methylations incorporated by RsmE, RsmF, and RsmH/ RsmI form a cluster of three modified 16S rRNA nucleotides (m3U1498, m5C1407, and m4Cm1402) surrounding the decoding center of the 30S subunit. Given their common substrate requirement of a late-stage intermediate 30S subunit, these enzymes likely act contemporaneously during subunit biogenesis, but whether there exists a required modification order is unknown. Here, using hypomethylated 30S subunits obtained from a collection of rsmH/I/E/F-deleted Escherichia coli strains, we identify RsmF activity to be highly dependent on prior modification of h44 both in vitro and in E. coli. RsmF activity on hypomethylated 30S subunits could be partially rescued by prior in vitro methylation using RsmE and RsmH, indicating that incorporation of these methyl groups directly shapes h44 for recognition by RsmF. RNA structure probing using selective 2'-hydroxyl acylation analyzed by primer extension and mutational profiling and molecular dynamics simulations reveal specific alterations in 16S rRNA structure and dynamics in the absence of the m4C1402 (RsmH) and m3U1498 (RsmE) modifications that likely restrict RsmF action. These studies thus uncover a previously unappreciated "order of operations" for 16S rRNA modification during ribosome biogenesis with important implications for studies on the collective functions of these modifications.

DOI: https://doi.org/10.1093/nar/gkag1005
J Biochem. 2026 Oct 31. pii: mvag077. [Epub ahead of print]

RNA recognition and cleavage in archaeal ribosome biogenesis: insights from FAU-1.

Takuhiro Ito.

  Ribosomal RNA maturation requires nucleases that recognize appropriate precursors and cleave them at defined stages of ribosome assembly. How these activities are organized in archaea remains elusive. Kawai and colleagues determined the crystal structure of the archaeal ribonuclease FAU-1, revealing a homotrimer with peripheral RNA-binding domains and a central assembly formed by its C-terminal domains. The structure identifies similarities to the RNA-recognition region of bacterial ribonuclease (RNase) E while exposing substantial differences in overall architecture. Subsequent work assigned FAU-1 to the RNase W family and demonstrated a catalytic role for its C-terminal domain. Together, these studies illustrate how related RNA-recognition elements can operate within distinct nuclease architectures. They also raise questions about the relationship between oligomerization, substrate selection and catalytic activation. Resolving these questions will require analysis of physiological RNA substrates and their associated proteins, connecting the structures of individual processing enzymes to the assembly of functional ribosomes.

Keywords:  FAU-1; RNase W; archaea; rRNA processing; ribosome biogenesis

DOI:  https://doi.org/10.1093/jb/mvag077
Biochem Biophys Res Commun. 2026 Oct 24. pii: S0006-291X(26)01572-X. [Epub ahead of print]841 154806

Nuclear respiratory factor 1 supports NPM1 expression and contributes to the regulation of a subset of ribosome biogenesis genes.

Mizuha Mochida, Keito Nakahira, Mitsuru Okuwaki.

  Nucleolar proteins support ribosome biogenesis in proliferating cells, but their expression levels have not been systematically compared with those of ribosomal proteins. We analyzed Human Protein Atlas RNA-sequencing data from 1132 cancer cell lines, comparing 280 ribosome biogenesis-related genes with 88 ribosomal protein (RP) genes. RP genes were generally highly expressed, whereas expression of ribosome biogenesis-related genes varied widely. NPM1 was the most highly expressed gene in the latter group, with expression comparable to that of many RP genes. To investigate how NPM1 expression is maintained, we analyzed its promoter using reporter assays and identified a proximal sequence that supports promoter activity. A dominant-negative nuclear respiratory factor 1 (NRF1) mutant reduced reporter activity when its putative target sequence was present. NRF1 knockdown decreased endogenous NPM1 mRNA level, and chromatin immunoprecipitation (ChIP) detected NRF1 at the proximal NPM1 promoter. Analysis of public NRF1 ChIP-sequence data revealed promoter-proximal occupancy at a subset of ribosome biogenesis-related genes, including NPM1, FBL, and DKC1. NRF1 binding to the FBL and DKC1 promoters was also confirmed by ChIP assay, and expression of both genes decreased upon NRF1 knockdown. These findings identify NRF1 as a contributor to the expression of a subset of ribosome biogenesis-related genes.

Keywords:  NPM1; NRF1; Ribosomal protein; Ribosome biogenesis; Transcription regulation

DOI:  https://doi.org/10.1016/j.bbrc.2026.154806
bioRxiv. 2026 Oct 09. pii: 2026.10.08.757657. [Epub ahead of print]

Molecular sterics guide tmRNA translocation on the ribosome.

George Wanes, Kenneth C Keiler, Christine M Dunham, Paul C Whitford.

Translation of defective mRNA transcripts can lead to the formation of stalled "non-stop" ribosome complexes. To rescue these ribosomes, bacteria have evolved a mechanism called trans -translation that is mediated by transfer-messenger RNA (tmRNA) and small protein B (SmpB). During the translocation step of trans -translation, the stalled mRNA is ejected and the reading frame found in the mRNA-like domain (MLD) of tmRNA is loaded into the mRNA channel. The ribosome then translates the new template, thereby tagging the nascent protein for degradation. While structures of tmRNA-SmpB on the ribosome have been available for years, little is known about the molecular factors that govern the dynamics of tmRNA translocation. Here, we use an energetically smooth model (i.e. SMOG) to simulate translocation of tmRNA-SmpB, which reveals that the structure of the ribosome gives rise to a preferred sequence of conformational substeps. Specifically, the tRNA-like domain (TLD) translocates, then the MLD loads, and finally the C-terminal tail of SmpB rearranges. These steps are interdependent and associated with a range of sterically-induced barriers that regulate the kinetics. This provides a structural and energetic framework for understanding, and ultimately controlling, the dynamics of trans -translation.

DOI: https://doi.org/10.64898/2026.10.08.757657
Cells. 2026 Oct 16. pii: 1888. [Epub ahead of print]15(20):

Defective Ribosome Biogenesis Drives Tubular Senescence and Renal Fibrosis via IRBC-p53 Activation.

Kaixin Song, Hua Su.

  Impaired ribosome biogenesis (RiBi) triggers the impaired ribosome biogenesis checkpoint (IRBC), a nucleolar stress pathway that stabilizes p53 and induces cellular senescence. Whether RiBi dysfunction directly drives renal interstitial fibrosis (RIF) remains unknown. Here, we combined human IgA nephropathy biopsies, murine fibrosis models, and cultured proximal tubular epithelial cells treated with the RNA polymerase I inhibitor CX5461, the p53 inhibitor pifithrin-α, siRNA-mediated POLR1A knockdown, and the DNA-damaging agent etoposide to dissect the RiBi-IRBC-p53-senescence axis. We identified defective rDNA transcription in the proximal tubules of fibrotic human kidneys and in experimental fibrosis models. Pharmacological RiBi inhibition with CX5461 induced RIF prior to functional decline. Mechanistically, RiBi impairment promoted RPL5/RPL11 binding to HDM2, stabilized p53, upregulated p21, and induced G2/M arrest, which was rescued by pifithrin-α. Genetic silencing of POLR1A recapitulated IRBC activation and senescence without causing DNA damage. Time-course analysis showed only marginal γ-H2AX elevation by CX5461 versus robust induction by etoposide. Importantly, etoposide-induced DNA damage failed to enhance RPL5/RPL11-HDM2 binding, suggesting that IRBC activation is not a general consequence of the DNA damage response. Collectively, impaired RiBi drives RIF mainly through the IRBC-p53-senescence axis under our experimental conditions, providing a mechanistic framework for understanding organ toxicities associated with RNA Pol I inhibition.

Keywords:  DNA damage response; cellular senescence; impaired ribosome biogenesis checkpoint; kidney fibrosis; p53; ribosome biogenesis

DOI:  https://doi.org/10.3390/cells15201888
Nucleic Acids Res. 2026 Oct 24. pii: gkag1060. [Epub ahead of print]54(20):

Dynamic phosphorylation of TCOF1 controlled by CK2 and PPM1D regulates nucleolar condensation and RNA polymerase I activity.

Natalie Palkova, Matous Palek, Marketa Brodinova, Zuzana Chalupova, Radka Storchova, Jana Jasprova, Pavel Talacko, Dusan Cmarko, Libor Macurek.

The nucleolus is a membrane-less organelle essential for ribosomal DNA (rDNA) transcription and ribosome biogenesis, yet the mechanisms regulating its dynamic assembly remain incompletely understood. Here, we identify the phosphatase protein phosphatase magnesium-dependent 1 delta (PPM1D) as a key regulator of the nucleolar architecture via dephosphorylation of the scaffold protein TCOF1. By combining super-resolution microscopy and domain mapping, we show that PPM1D localizes to the nucleolus through a conserved motif at the C-terminus. Phosphoproteomic analysis and structural modeling revealed that PPM1D targets casein kinase 2 (CK2)-phosphorylated sites within the low-complexity repeat domain of TCOF1, which impacts its interaction with RNA polymerase I (Pol I), immobilization in the fibrillar centres, and nucleolar condensation. Disruption of the phosphorylation balance by loss of PPM1D or inhibition of CK2 leads to nucleolar disorganization and reduced rDNA transcription. Finally, we demonstrate that pharmacological inhibition of PPM1D sensitizes cells to RNA Pol I inhibitors, in both p53-dependent and -independent contexts. Together, we uncover a reversible phosphorylation switch that governs TCOF1 dynamics and its nucleolar function, with potential implications for targeting ribosome biogenesis in cancer.

DOI: https://doi.org/10.1093/nar/gkag1060
bioRxiv. 2026 Sep 01. pii: 2026.08.31.748072. [Epub ahead of print]

RSV competes with the host for translational machinery without a host shutoff strategy.

Kyra Kerkhofs, Nicholas R Guydosh.

RNA viruses often enhance ribosome recruitment to their own mRNAs through non-canonical sequence elements or by degrading host mRNA. Respiratory syncytial virus (RSV) produces mRNAs with host-like features, including 5'-cap and poly(A) tail. Therefore, the virus lacks an obvious mechanism to preferentially protect its own mRNAs or recruit ribosomes. Furthermore, it remains unknown how RSV interacts with antiviral defense pathways that would reduce cap-dependent translation. Using spike-in normalized sequencing of total and ribosome-associated RNA, we found that RSV does not appear to evoke any host shutoff mechanisms to limit the expression of host genes. These findings show that RSV manages to make use of available ribosomes by competing effectively with host mRNAs and any translational shutoff mechanism would be detrimental. Consistent with this, we found that following activation of antiviral host pathways that reduce cap-dependent translation, translation of RSV mRNAs is decreased to the same extent as host mRNAs. Furthermore, we found that RSV infection does not trigger the dsRNA-activated kinase PKR (which initiates the ISR) and OAS (activates endonuclease RNase L) pathways. These data support a model in which RSV achieves viral protein production, not though inhibiting the host, but by successfully competing with host mRNAs and avoiding activation of antiviral pathways.
Highlights: RSV does not induce host mRNA degradationRSV mRNAs effectively recruit ribosomes throughout infection and cause some reduction in host mRNA translationRSV mRNAs depend on eIF4E for translation and are stabilized independently of LARP1 when eIF4E is depletedRSV avoids strong activation of the ISR and OAS/RNaseL pathways instead of directly inhibiting their activation.

DOI: https://doi.org/10.64898/2026.08.31.748072
Cell Rep. 2026 Oct 29. pii: S2211-1247(26)01305-7. [Epub ahead of print]45(11): 118226

CSE1L enrichment in pediatric and young adult acute myeloid leukemia reveals a ribosomal export dependency.

Grace Egan, Amit Kumar, Veronique Voisin, Rose Hurren, Ali Chegini, Dakai Ling, Geethu Emily Thomas, Yongran Yan, Yue Feng, Nathan Duong, Dilshad Khan, Chaitra Sarathy, Yulia Jitkova, Suraj Bansal, Andy G X Zeng, Fieke W Hoff, Steven M Kornblau, John E Dick, Johann Hitzler, Aaron D Schimmer.

  Proteins shuttle between the nucleus and cytoplasm through the nuclear pore and via nuclear transport receptors, termed importins and exportins. Although genetic alterations involving nucleoporins are enriched in pediatric, adolescent, and young adult (AYA) acute myeloid leukemia (AML), nucleocytoplasmic transport has not been extensively studied in this disease. We discover that genes encoding nucleocytoplasmic transport pathway components (Kyoto Encyclopedia of Genes and Genomes [KEGG]: hsa03013) are enriched in AML cells from younger patients (≤40 years). Within this pathway, CSE1L is the highest expressed exportin in pediatric/AYA AML and shows minimal expression in hematopoietic stem cells (HSCs). CSE1L depletion reduces leukemic cell growth, proliferation, and clonogenic capacity, targeting leukemia stem cells while sparing normal HSCs. Mechanistically, we identify a novel Ran-GTP-dependent role for CSE1L in regulating pre-60S ribosomal subunit export in AML. Collectively, these data identify nucleocytoplasmic transport and ribosomal subunit export as enriched dependencies in pediatric/AYA AML and establish CSE1L-mediated export as a leukemic vulnerability.

Keywords:  CP: cancer; CSE1L; XPO2; acute myeloid leukemia; childhood AML; nuclear export; nucleocytoplasmic transport; pediatric AML; ribosomal subunit export; ribosome biogenesis

DOI:  https://doi.org/10.1016/j.celrep.2026.118226
Nucleic Acids Res. 2026 Oct 24. pii: gkag1022. [Epub ahead of print]54(20):

EWSR1 associates with the 40S ribosomal subunit and represses translation to maintain endoplasmic reticulum homeostasis.

Zahrat El Oula Hassoun, Loic Ongena, Lionel Condé, Bartimée Galvan, Grégory Fettweis, Michelle Lion, Romuald Soin, Jonathan Bruyr, Florence Lemaitre, Marc Thiry, Emeline Mariavelle, Margaux Claes, Arnaud Blomme, Gerben Menschaert, Jonas Dehairs, Véronique Kruys, Cyril Gueydan, Tina M O'grady, Johannes V Swinnen, Sylvain de Breyne, Théophile Ohlmann, Jean-Claude Twizere, Yvette Habraken, Franck Dequiedt.

FET family proteins (FUS, EWSR1, and TAF15) have garnered significant attention due to their involvement in oncogenic fusions and mutations in various cancers and neurodegenerative disorders. Although these highly conserved RNA-binding proteins are widely described as multifunctional regulators of gene expression, their precise molecular functions remain incompletely understood. Here, we uncover a previously unrecognized role for EWSR1 as a selective translational repressor in cancer cells. EWSR1 specifically targets mRNAs involved in lipid metabolism and endoplasmic reticulum (ER) homeostasis. Loss of EWSR1 disrupts ER morphology and impairs activation of the unfolded protein response of the ER (UPRER). Mechanistically, EWSR1 represses translation upon association with target mRNAs, and its conserved region spanning two arginine-glycine-glycine (RGG) boxes contributes to association with the 40S ribosomal subunit. These findings define a novel role for EWSR1 in post-transcriptional gene regulation and suggest that perturbations in its translational activity may underlie the pathogenesis of FET-associated diseases.

DOI: https://doi.org/10.1093/nar/gkag1022
bioRxiv. 2026 Sep 03. pii: 2026.09.01.748611. [Epub ahead of print]

Ribosomal proteins are major substrates of starvation-induced endosomal microautophagy in Drosophila.

Prasoon Jaya, Satya Surabhi, Jennifer Aguilan, Simone Sidoli, Andreas Jenny.

Maintenance of cellular homeostasis requires tight coordination between protein synthesis and degradation, particularly at old age and under conditions of stress including starvation. Autophagy contributes to sustain this balance by degrading cytoplasmic proteins and organelles. It thus is essential to prevent the accumulation of damaged proteins and organelles and to recycle nutrients. Of the three forms of autophagy, macroautophagy, chaperone mediated autophagy, and (endosomal) microautophagy (e-MI), the latter remains the least well understood. During e-MI, cytosolic substrate proteins are captured into late endosomes via ESCRT-dependent multivesicular body formation and then degraded in late endosomes or lysosomes. e-MI is thought to contribute to protein quality control under basal conditions and under stress. Importantly, very little is known about the endogenous substrates of e-MI in flies and thus about its physiological role. Performing integrative multi-omic analyses in Drosophila larval fat body that has functions similar to mammalian liver and adipose tissue, we identified 153 high-confidence endogenous e-MI substrates with the degradation of ribosomal proteins by e-MI being the most strongly affected functional category. Generally, we found that starvation caused the depletion of proteins involved in translation, aminoacyl-tRNA synthesis, and ribosomal biogenesis, without affecting their level of transcripts. Importantly, we observe a striking specificity between e-MI and macroautophagy, as the two pathways largely target distinct protein sets including different subsets of ribosomal proteins. Our metabolomic analysis further shows that genetic inhibition of e-MI reverses the reduced levels of amino acid caused by starvation. Together, our findings reveal ribosome turnover as a central physiological function of Drosophila e-MI and establish e-MI as a pathway driving metabolic adaptation during starvation.
HIGHLIGHTS: Proteomic and metabolomic analysis of Drosophila fat body under starvation stress Systematic identification of endosomal microautophagy (e-MI) substrates.Ribosomal proteins are a major target of e-MI.e-MI and macroautophagy degrade distinct proteins incl. different ribosomal ones.Prolonged starvation alters amino acid levels.

DOI: https://doi.org/10.64898/2026.09.01.748611
Cell Metab. 2026 Oct 28. pii: S1550-4131(26)00439-0. [Epub ahead of print]

Arginine rewires eIF4F translation initiation to overcome fever-induced CAR T cell dysfunction.

Taisuke Kondo, Makoto Ando, Josquin Moraly, Justyn DuSold, Abdallah Abdelmaksoud, Hannah W Song, Lakshmi Balagopalan, Dongya Jia, Laetitia Racine, Andy D Tran, Sooraj Achar, Serifat O Adebola, Pedro Gonzalez-Menendez, John Buckley, Anjali Chandroth, Alka Dwivedi, Nikolaos Svoronos, Angela Su, Christopher D Chien, Alexander D Clark, Xiyuan Zhang, Bonnie Yates, King Chan, Stephen D Fox, Xia Xu, Nicholas P Restifo, Neeraja Syed, Michael C Kelly, Michael Kruhlak, Yuki Kagoya, Rémy Bosselut, Jack F Shern, Thorkell Andresson, Valérie Dardalhon, Craig J Thomas, Steven L Highfill, Nirali N Shah, Grégoire Altan-Bonnet, Naomi Taylor.

  Chimeric antigen receptor (CAR) T cell therapy has revolutionized treatment of hematological malignancies, but cytokine release syndrome (CRS) remains a major toxicity. Fever-a hallmark of CRS-has been understudied as a modifier of therapeutic efficacy. In a retrospective cohort of patients with B cell acute lymphoblastic leukemia treated with CD22-directed CAR T cells (NCT02315612), sustained high-grade fever inversely correlated with clinical response. Mechanistically, experimental hyperthermia impaired proximal CAR signaling, reduced cytotoxicity, and compromised metabolic fitness through dysregulated arginine metabolism. Arginine supplementation restored CAR T cell function following hyperthermic stress and enhanced cytotoxicity under normothermic conditions. This effect required mTOR-dependent recruitment of the eIF4F translation-initiation complex and downstream c-MYC-driven metabolic reprogramming. Importantly, arginine enhanced good manufacturing practice (GMP)-manufactured CAR T cell function under normothermia, while oral supplementation improved in vivo efficacy. These findings identify metabolic control of translation as a fever-sensitive checkpoint and establish arginine supplementation as a tractable strategy to enhance CAR T cell efficacy.

Keywords:  CD22; arginine; c-MYC; chimeric antigen receptor T cell therapy; cytokine release syndrome; fever; mTOR; metabolic fitness; mitochondrial function; translation initiation

DOI:  https://doi.org/10.1016/j.cmet.2026.10.001
bioRxiv. 2026 Oct 09. pii: 2026.10.05.756038. [Epub ahead of print]

RiboFlow v2: a configurable ribosome profiling pipeline reveals measurements sensitive to read-mapping methodology.

Daniel Nguyen, Can Cenik.

Ribosome profiling experiments capture a snapshot of translation by sequencing ribosome-protected fragments (RPFs). Alignment to a well-curated transcriptome captures most RPF signal, but can miss ribosome activity when expressed exons are absent from the reference. Genome alignment of RPFs expands the detectable sequence space, but can expose ambiguity between homologous loci. Existing workflows often couple reference choice with the handling of ambiguously mapped reads, making it difficult to isolate the effects of either decision on downstream analyses. Here, we developed RiboFlow v2 by adding genome alignment and configurable handling of multimapping reads to the existing transcriptome workflow. Using 24 human ribosome profiling libraries and their matched RNA-seq data, we found that nucleotide-level coverage at matched coding-sequence positions and translation efficiency (TE) were broadly concordant between alignment strategies under stringent alignment filters. Even under these conditions, individual genes showed substantial differences in coverage and TE estimates. These differences included coverage in alternative exons absent from selected transcripts and ambiguous alignments between protein-coding genes and processed pseudogenes. Clustering genes by read-assignment patterns identified groups associated with pseudogene prevalence and highlighted shared exonic sequence among reference transcripts as a source of alignment discrepancies. RiboFlow v2 extends the analysis beyond selected reference transcripts and enables identification of genes whose ribosome coverage and abundance estimates depend on reference composition and how ambiguously mapped reads are handled.

DOI: https://doi.org/10.64898/2026.10.05.756038
Nat Commun. 2026 Oct 29. pii: 11037. [Epub ahead of print]17(1):

Antimicrobial peptides derived from Nemuri induce ribosomal condensation to inhibit translation.

Suguru Nishinami, Moynul Hasan, Tatsuya Niwa, Tomohiro Inui, Takeshi Yokoyama, Hiroto Otsuki, Yuta Ogasawara, Hiroka Sugai, Yuta Otobe, Masato Machida, Mohammed Abdelaziz, Natsumi Ageta-Ishihara, Ryohei Sasaki, Yoshimasa Ishizaki, Kenji Iwasaki, Yuko Fujioka, Tomokazu Ohishi, Shinji Kajimoto, Takakazu Nakabayashi, Yoshikazu Tanaka, Hikari Yoshitane, Hiroyuki Kumeta, Amita Sehgal, Masayuki Igarashi, Nobuo N Noda, Hirofumi Toda.

Antibiotic resistance is a global health threat requiring antimicrobials with alternative modes of action. Growing evidence indicates that bacteria organize key intracellular processes through biomolecular condensates and other forms of spatial organization, yet whether such spatial organization can be exploited as an antimicrobial target remains unclear. Here, we identify intrinsically disordered antimicrobial peptides, generated from the Drosophila sleep-inducing protein Nemuri, that inhibit bacterial growth by targeting ribosomal organization. Mechanistically, these peptides enter bacterial cells without overt membrane disruption and accumulate in ribosome-rich regions, where they bind broadly to RNA and ribosomal surfaces through multivalent interactions. This engagement remodels ribosome-rich regions into condensates with reduced ribosomal mobility, thereby suppressing global protein synthesis and distinguishing these peptides from canonical site-specific ribosome-targeting antibiotics. Furthermore, Nemuri-derived peptides exhibit broad-spectrum antimicrobial activity, including activity against drug-resistant pathogens, with low cytotoxicity toward Drosophila and mammalian cells. Together, our findings identify the organization and material dynamics of bacterial ribosomes as a biophysical vulnerability that can be exploited by antimicrobial peptides, revealing how a naturally evolved metazoan host-defense system turns intracellular organization itself into an antibacterial target.

DOI: https://doi.org/10.1038/s41467-026-78960-5
J Mol Cell Biol. 2026 Oct 30. pii: mjag046. [Epub ahead of print]

KDM3B regulates hair follicle stem cell differentiation by activating the mTOR-dependent translation program.

Chaofan Lv, Hao Wang, Fan Meng, Meijun Zhou, Jiaqi Fan, Runsheng Chen, Jian Zhang, Haisheng Yu, Yan Qin.

  Hair follicle (HF) development and regeneration rely on the precise differentiation of hair follicle stem cells (HFSCs), a process governed by epigenetic regulation. While nutrient-sensing mTOR signaling is known to be pivotal, the upstream epigenetic triggers and the downstream events orchestrating this pathway remain poorly defined. The histone H3K9me2 demethylase KDM3B has recently emerged as a key player in stem cell fate decisions. By integrating recent high-throughput sequencing data and employing a conditional knockout mouse model, we demonstrated that KDM3B was essential for HFSC differentiation, as its loss led to severe defects in postnatal HF development and HFSC differentiation. Mechanistically, we identified the mTOR signaling pathway and its downstream protein translation machinery as the primary effectors of KDM3B. KDM3B activated mTOR complex 1 (mTORC1) signaling, which subsequently upregulated the TOP mRNA-binding protein LARP1 to drive ribosome biogenesis and global protein synthesis. Our work delineated a complete 'KDM3B-mTORC1-LARP1-ribosome' axis that functionally integrates epigenetic control with translational regulation to direct HFSC differentiation. These findings not only establish KDM3B as a novel key regulator in skin epithelia but also provide the first comprehensive mechanistic link from an epigenetic modifier through the mTOR pathway to the ribosomal translation program within the HF model.

Keywords:  AKT–mTOR pathway; KDM3B; hair follicle differentiation; hair follicle stem cells; ribosome

DOI:  https://doi.org/10.1093/jmcb/mjag046
Nucleic Acids Res. 2026 Oct 24. pii: gkag1019. [Epub ahead of print]54(20):

Structural probing of RNA hairpins quantifies protein occupancy on RNA and links it to function in human cells.

Abby R Thurm, Tanya H Nguyen, Jesus Damian Torres Campos, Matthew Mansfield, Lacramioara Bintu, Lauren D Hagler.

RNA structures that form inside living cells govern processes ranging from translation to RNA decay, many of which are controlled by RNA-binding proteins (RBPs). Because RBP specificity can depend on both RNA sequence and folding, traditional pulldown-based methods often obscure the structural context of bound RNAs. Here, a quantitative framework based on dimethyl sulfate mutational profiling and sequencing was established to directly measure RNA structure and RBP binding in human cells at single-nucleotide resolution. Applied to a 1600-member MS2 hairpin library, this approach revealed that RNA folding is the strongest determinant of MS2 coat protein (MCP) recognition in the MS2-MCP system, requiring formation of a stable hairpin and a consensus loop sequence, with stem length or GC content contributing primarily through their effect on hairpin folding. An in-cell occupancy model was derived to quantify fractional binding from structural readouts. Complementary systems using degron-tuned MCP and a downregulatory MCP fusion demonstrated binding behavior under subsaturating protein concentrations and showed that inferred occupancy quantitatively predicts RNA degradation efficiency. Together, these results establish a quantitative strategy for measuring RBP-RNA specificity and affinity directly in cells, using the MS2-MCP system to link RNA structure, protein occupancy, and regulatory outcome.

DOI: https://doi.org/10.1093/nar/gkag1019
RNA. 2026 Oct 29. pii: rna.081163.126. [Epub ahead of print]

m⁶A presence and dosage are associated with IGF2BP2 binding, RNA abundance, and translation in mouse heart and liver.

Jiaying Liu, Tingxuan Xu, Weihao Pan, Xinjie Li, Sheng Liu, Xin Li, Xuan Jiang.

  N6-methyladenosine (m⁶A), the most prevalent internal modification in mammalian mRNA, contributes to post-transcriptional gene regulation, yet how m⁶A presence and modification intensity relate to gene expression during development remains incompletely understood. Here, by integrating m⁶A-seq, RNA-seq, IGF2BP2 RIP-seq, and Ribo-seq data across developmental trajectories of murine heart and liver, we identify a genome-wide presence-dosage pattern of m⁶A-associated gene regulation. m⁶A-modified transcripts generally show higher baseline expression than unmodified transcripts, whereas increasing modification intensity within m⁶A-modified transcripts is associated with reduced transcript abundance. This dual pattern is linked to the binding behavior of the m⁶A reader IGF2BP2: IGF2BP2 occupancy is enriched on m⁶A-modified transcripts but decreases with higher methylation intensity. Structural equation modeling further supports layered associations among m⁶A status, IGF2BP2 binding, transcript abundance, and ribosome occupancy. Regional analysis of m⁶A peaks also suggests position-dependent relationships with translation efficiency, with 3' UTR m⁶A associated with higher TE and CDS m⁶A associated with lower TE. Together, our study provides a quantitative multi-omic framework for understanding how m⁶A presence and dosage are associated with gene expression and translation during tissue development, and suggests IGF2BP2 binding as a potential mediator of these relationships.

Keywords:  IGF2BP2; RNA modification; epitranscriptomics; m⁶A methylation; ribosome profiling

DOI:  https://doi.org/10.1261/rna.081163.126
Nat Cell Biol. 2026 Oct 29.

Methylated eEF1A selectively decodes mRNA to shape cancer proteomes.

Shuo Liu, F Aaron Cruz-Navarrete, Simone Hausmann, Krzysztof J Szkop, Sabeen Ikram, Ryan A Brady, Xiaoyin Lu, Rui Dong, Julia Vu, Natasha M Flores, Emily Zahn, Julia Thompson, Ben A Garcia, Ola Larsson, Ivan Topisirovic, Scott C Blanchard, Or Gozani, Pawel K Mazur.

Although mRNA decoding efficiency influences protein synthesis, it remains unknown whether the translation elongation machinery harbours intrinsic mechanisms that selectively modulate codon decoding to shape proteomes. Here we show that METTL13-catalysed dimethylation of the elongation factor eEF1A at lysine 55 (eEF1AK55me2) enhances decoding of select codons, preferentially increasing pro-oncogenic protein synthesis to promote tumorigenesis and targeted therapy resistance. Proteomic profiling and single-molecule imaging reveal that eEF1AK55me2 increases decoding efficiency, particularly for under-represented codons with weak wobble-position base pairing. In cancer cells, METTL13 knockdown reduced translation of oncogenic mRNA enriched in eEF1AK55me2-dependent codons, including KRAS; synonymous recoding with eEF1AK55me2-independent codons reversed this effect. METTL13 loss inhibited the growth of KRASG12C inhibitor (sotorasib)-resistant lung adenocarcinoma syngeneic tumours and patient-derived xenografts. In relapsed autochthonous KRASG12C-driven lung adenocarcinoma, METTL13 ablation mitigated sotorasib resistance and significantly extended survival in vivo. Among patients receiving a KRASG12C inhibitor, inferred METTL13 activity was associated with inferior clinical response. These findings identify an eEF1AK55me2-mediated mRNA decoding mechanism promoting selective oncogenic protein synthesis and suggest METTL13 targeting may counteract KRAS-inhibitor resistance.

DOI: https://doi.org/10.1038/s41556-026-02085-6
Cell Rep. 2026 Oct 29. pii: S2211-1247(26)01285-4. [Epub ahead of print]45(11): 118206

ALS-linked FUS mutation impairs GEMIN5-dependent mRNA recruitment to neuronal late endosomes.

Adriano Setti, Lorenzo Stufera Mecarelli, Tiziana Santini, Angelo D'Angelo, Vittorio Padovano, Erika Vitiello, Francesco Castagnetti, Julie Martone, Davide Mariani, Irene Bozzoni.

  Neurons depend on tightly regulated positioning of cellular components to maintain long-distance signaling, but the mechanisms guiding specific mRNAs to distant regions remain unclear. Here, we show that late endosomes function as selective RNA carriers in human motor neurons and uncover the molecular logic guiding their loading. Using APEX2-mediated proximity labeling, we identify the external transcriptome of RAB7A-positive endosomes and find a specific population of mRNAs enriched for endosomal, axonal, and synaptic functions. We find that mRNAs enriched in RAB7A endosomes contain evolutionarily conserved 5'UTRs that act as localization signals, and that the RNA-binding protein GEMIN5 interacts with these regions to promote endosomal RNA recruitment. Finally, we show that there is a conspicuous loss of endosome-associated transcripts in amyotrophic lateral sclerosis-associated conditions, accompanied by the mislocalization of GEMIN5 from endosomes. These findings uncover fundamental principles of RNA compartmentalization and highlight endosomal mRNA loading as a vulnerable axis in neuronal homeostasis.

Keywords:  5'UTR; ALS; APEX2; CP: molecular biology; CP: neuroscience; FUS; GEMIN5; RAB7A; RNA compartmentalization; late endosomes; proximity labeling

DOI:  https://doi.org/10.1016/j.celrep.2026.118206
Cell Rep. 2026 Oct 26. pii: S2211-1247(26)01303-3. [Epub ahead of print]45(11): 118224

Role of Leu and Val synthesis in sensing mitochondrial nutrient and energy availability.

Jasmine Phan, Lincoln Gay, Ladislav Dokládal, Claudio De Virgilio, Leonardo Salcedo, Suprim Tha, Caitlyn Wandvik, Markus Babst.

  How cells integrate nutrient availability to coordinate metabolism and growth remains poorly understood. Here, we identify branched-chain amino acid (BCAA) synthesis as a metabolic sensing system linking mitochondrial activity to translational and transcriptional control. Yeast limits Leu and Val import and instead relies on their synthesis, allowing BCAA production to reflect mitochondrial anabolic capacity. Reduced Val synthesis activates Gcn2, whereas reduced Leu synthesis inhibits TORC1, together decreasing translation efficiency and restricting growth. This response lowers levels of the transcriptional repressor Mig1, suppressing the Warburg/Crabtree effect and promoting alternative carbon source utilization. Remarkably, pharmacological inhibition of Leu/Val synthesis induces this metabolic reprogramming even in nutrient-rich medium, indicating that mitochondrial BCAA synthesis can partially override other nutrient-sensing pathways. Thus, BCAA synthesis couples mitochondrial anabolic capacity to Gcn2 and TORC1 activity and, through translational control of transcription factor abundance, shapes cellular metabolism.

Keywords:  CP: metabolism; Gcn2; TORC1; Warburg effect; amino acid synthesis; diauxic shift; mitochondria; starvation

DOI:  https://doi.org/10.1016/j.celrep.2026.118224
Cell Rep. 2026 Oct 24. pii: S2211-1247(26)01244-1. [Epub ahead of print]45(11): 118165

Cryo-EM and biochemical characterization of a BRAF/CRAF heterodimer shows that the NtA motif negative charge is dispensable for RAF activation.

Byung Hak Ha, Emre Tkacik, Dimitrios Gazgalis, Hyelim Kang, Dong Man Jang, Sayan Chakraborty, Hyesung Jeon, Michael J Eck.

  Upon RAS-driven membrane recruitment, RAF kinases ARAF, BRAF, and CRAF are activated through homo- or heterodimerization to initiate MAP kinase signaling. Although RAF heterodimers drive physiologic and oncogenic signaling, they remain little studied structurally and biochemically. Here, we report the preparation, biochemical characterization, and cryo-EM structures of 14-3-3-bound BRAF/CRAF heterodimer complexes. The heterodimer exhibits kinetic parameters and RAF inhibitor sensitivities intermediate between, or closely matching, BRAF and CRAF homodimers. Cryo-EM structures reveal an organization identical to RAF homodimers, with an asymmetric interaction unique to the MEK1-bound structure in which the BRAF acidic NtA motif engages the CRAF RKTR motif. Mutagenesis reveals that replacing the acidic NtA sequence with basic RARA yields active dimers, showing that negative charge is dispensable for activity. Collectively, our findings suggest the NtA charge state influences RAF activity through effects on local backbone dynamics and inactive-state stability, rather than via stereospecific recognition across the dimer interface.

Keywords:  14-3-3; BRAF; CP: molecular biology; CRAF; Cryo-EM; MAP kinase pathway; RAF kinase; RAF1

DOI:  https://doi.org/10.1016/j.celrep.2026.118165
Nature. 2026 Oct 28.

Pharmacological inhibition of METTL1 as a therapy against solid and blood cancers.

Eliza Yankova, Alexandra Sapetschnig, Beth Thomas, Siân Evans, Maria Eleftheriou, Malgorzata Gozdecka, Harry Fischl, Teresa Brevini, Rachael Wilson, Sarah J Bucknell, Andrew Hutchin, Carmen M Livi, George Giotopoulos, Ryan Asby, Laura Bond, Aleksandra Azevedo, Natalie Webster, Jack Rogan, James Russell, Byron Andrews, Hendrik Weisser, Joanna Baxter, Judith López-Luis, Giovanna Mantica, Jake Tobin, Diego Lopez-Leon, Dean C Pask, Vidur Tandon, Richard Fosbeary, Sapphire Sawyer, Sunay Usluer, Nithila Joseph, Evangelia Stamou, Maria T Bejar, Yogeshkumar Malam, Roland Rad, Elisa Laurenti, Juan Li, Maria P Alcolea, David J Adams, Walid T Khaled, Fotios Sampaziotis, George S Vassiliou, Brian J P Huntly, Oliver Rausch, Konstantinos Tzelepis.

The N7-methylguanosine (m7G) modification is one of the most prevalent tRNA modifications, mainly catalysed by the METTL1-WDR4 protein complex1-4. The m7G methyltransferase METTL1 has been linked to oncogenic transformation and the maintenance of several aggressive malignancies; however, the clinical implications of therapeutically targeting a tRNA-modifying enzyme have not been established. Here we present the development and characterization of STM9005, a highly selective and potent first-in-class tRNA methyltransferase inhibitor of METTL1. Treatment of numerous cancer cell models (including leukaemia, melanoma, pancreatic carcinoma, oesophageal cancer and small cell lung carcinoma) with STM9005 blocks cell growth, causes differentiation changes and dysregulates cell cycle progression. These cellular effects were accompanied by a selective decrease in m7G on a subset of tRNAs and a reduction in their expression levels, which impacted the translation of oncogenic mRNAs. We show that pharmacological inhibition of METTL1 in vivo impairs tumour growth and significantly prolongs survival in multiple mouse cancer models of different tissue origin. Collectively, our results provide a strong proof of concept that targeting of tRNA methylation is a promising avenue of anti-cancer therapy and illustrate that catalytic inhibition of METTL1 represents a therapeutic strategy against a number of aggressive malignancies.

DOI: https://doi.org/10.1038/s41586-026-11178-z
Sci Adv. 2026 Oct 30. 12(44): eaej4259

The nonsense-mediated decay RNA-surveillance pathway facilitates the hypoxia response by C. elegans.

Calista Diehl, H Robert Horvitz.

Hypoxia (decreased O2) induces physiological, metabolic, and behavioral changes. The major hypoxia response pathway is conserved from nematodes to mammals and is driven by activation of the HIF (hypoxia inducible factor) family of transcription factors. Despite a fundamental role of the HIF pathway in regulating cellular homeostasis in response to hypoxic stress, interactions between the HIF pathway and cellular quality control pathways are largely unknown. Using an unbiased genetic screen, we found that in C. elegans nonsense-mediated decay (NMD), an evolutionarily conserved mechanism of RNA surveillance, acts in parallel to HIF-1 to selectively enhance specific aspects of the response to HIF-1 activation, possibly through coregulation of a distinct subset of HIF-1-up-regulated genes. Our findings reveal a functional integration between oxygen sensing and RNA surveillance and establish NMD as a key regulator of specific aspects of the HIF-1-driven transcriptional program and physiological response.

DOI: https://doi.org/10.1126/sciadv.aej4259