Pub Date : 2025-12-18DOI: 10.1016/j.molcel.2025.11.016
Ting Zhang, Chen Dong
In a recent Nature paper, Yi et al.1 uncover that a noncanonical proteotoxic stress response (PSR) in exhausted T cells (Tex), termed “Tex-PSR,” drives T cell exhaustion. This response is characterized by sustained global protein synthesis, accumulation of protein aggregate, and selective upregulation of chaperone proteins.
{"title":"Stress to exhaustion: Proteotoxicity in T cells","authors":"Ting Zhang, Chen Dong","doi":"10.1016/j.molcel.2025.11.016","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.016","url":null,"abstract":"In a recent <em>Nature</em> paper, Yi et al.<span><span><sup>1</sup></span></span> uncover that a noncanonical proteotoxic stress response (PSR) in exhausted T cells (Tex), termed “Tex-PSR,” drives T cell exhaustion. This response is characterized by sustained global protein synthesis, accumulation of protein aggregate, and selective upregulation of chaperone proteins.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"7 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145778078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.molcel.2025.11.027
Adel Avetisyan, Ernesto Manzo, Marc R. Freeman
In a recent issue of Cell, Wang et al.1 found that the pro-degenerative NAD+ hydrolase SARM1 can bind and be activated by dsDNA. This expands potential roles for SARM1 to sensing DNA damage or viruses and activating cell death.
{"title":"SARM1 as a dsDNA detector to sense nuclear damage and viruses to drive cell death","authors":"Adel Avetisyan, Ernesto Manzo, Marc R. Freeman","doi":"10.1016/j.molcel.2025.11.027","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.027","url":null,"abstract":"In a recent issue of <em>Cell</em>, Wang et al.<span><span><sup>1</sup></span></span> found that the pro-degenerative NAD<sup>+</sup> hydrolase SARM1 can bind and be activated by dsDNA. This expands potential roles for SARM1 to sensing DNA damage or viruses and activating cell death.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"48 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bacteriophages (phages) are major drivers of bacterial population dynamics, yet the significance of post-transcriptional regulation during infection remains largely unexplored. Central to this regulatory layer are small RNAs (sRNAs), which regulate target mRNAs via base-pairing, typically facilitated by RNA chaperones such as Hfq. Here, we applied RNA interaction by ligation and sequencing (RIL-seq) to comprehensively map the in vivo RNA-RNA interaction network in Escherichia coli during phage lambda infection. This analysis revealed extensive reprogramming of E. coli-E. coli interactions, phage-specific lambda-lambda interactions, and interkingdom interactions between phage and host RNAs. Among these, we identified a phage-encoded sRNA, phage replication enhancer sRNA (PreS), embedded within the early left operon. PreS regulates essential host genes, including dnaN, which encodes the DNA polymerase β sliding clamp. This regulation enhances DNA replication and fine-tunes the phage lytic cycle. These findings uncover an RNA-level regulatory layer in phage-host interactions and demonstrate how a phage-encoded sRNA can hijack host replication machinery to optimize infection.
{"title":"Phage-encoded small RNA hijacks host replication machinery to support the phage lytic cycle","authors":"Aviezer Silverman, Raneem Nashef, Reut Wasserman, Tamar Noy, Susan Born, Tianyou Yao, Yuncong Geng, Hila Rotbard, Adi Levkowitz, Yotam Kaufman, Ido Golding, Sahar Melamed","doi":"10.1016/j.molcel.2025.11.019","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.019","url":null,"abstract":"Bacteriophages (phages) are major drivers of bacterial population dynamics, yet the significance of post-transcriptional regulation during infection remains largely unexplored. Central to this regulatory layer are small RNAs (sRNAs), which regulate target mRNAs via base-pairing, typically facilitated by RNA chaperones such as Hfq. Here, we applied RNA interaction by ligation and sequencing (RIL-seq) to comprehensively map the <em>in vivo</em> RNA-RNA interaction network in <em>Escherichia coli</em> during phage lambda infection. This analysis revealed extensive reprogramming of <em>E. coli</em>-<em>E. coli</em> interactions, phage-specific lambda-lambda interactions, and interkingdom interactions between phage and host RNAs. Among these, we identified a phage-encoded sRNA, phage replication enhancer sRNA (PreS), embedded within the early left operon. PreS regulates essential host genes, including <em>dnaN</em>, which encodes the DNA polymerase β sliding clamp. This regulation enhances DNA replication and fine-tunes the phage lytic cycle. These findings uncover an RNA-level regulatory layer in phage-host interactions and demonstrate how a phage-encoded sRNA can hijack host replication machinery to optimize infection.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"1 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145778080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-10DOI: 10.1016/j.molcel.2025.11.018
Kensuke Ishiguro, Karin Midorikawa, Naoki Shigi, Satoshi Kimura, Aivar Liiv, Takeshi Yokoyama, Takuhiro Ito, Mikako Shirouzu, Jaanus Remme, Kenjyo Miyauchi, Tsutomu Suzuki
Ribosomal RNAs (rRNAs) contain various modifications that play critical roles in ribosome assembly and function. Here, we discovered two stereoselective methylations of the rRNA backbone in the peptidyl-transferase center (PTC) of the 50S subunit of Escherichia coli cultured under anaerobic conditions. Methylation occurs at carbon 5'(S) of ribose moieties of dihydrouridine at position 2449 (D5Sm2449) and 2'-O-metylcytidine at position 2498 (Cm5Sm2498). We identified the rlmX gene, encoding a cobalamin-dependent radical S-adenosylmethionine (SAM) methyltransferase responsible for these methylations. Intriguingly, D5Sm2449, Cm5Sm2498, and 5-hydroxycytidine (ho5C2501) in the PTC were elevated under anaerobic growth conditions. A double knockout strain lacking rlmX and rlhA (responsible for ho5C2501) impaired anaerobic growth. Biochemical studies showed that these rRNA modifications stimulate protein synthesis. The cryoelectron microscopy (cryo-EM) structure of the ribosome indicated that these hypoxia-induced modifications stabilize the P-site and the PTC. These findings demonstrate that ribosomes are activated by hypoxia-induced modifications to enhance translational capability and thereby survival, under anaerobic conditions.
核糖体rna （rrna）包含各种修饰，这些修饰在核糖体的组装和功能中起关键作用。在这里，我们发现在厌氧条件下培养的大肠杆菌50S亚基的肽基转移酶中心（PTC）的rRNA主干有两个立体选择性甲基化。甲基化发生在2449 （D5Sm2449）和2498 （Cm5Sm2498）位置的2'- o -甲基胞苷核糖部分的碳5'(S)处。我们确定了rlmX基因，编码负责这些甲基化的钴胺依赖性自由基s -腺苷甲硫氨酸（SAM）甲基转移酶。有趣的是，在厌氧生长条件下，PTC中的D5Sm2449， Cm5Sm2498和5-羟基胞苷（ho5C2501）升高。缺乏rlmX和rlhA（负责ho5C2501）的双敲除菌株会损害厌氧生长。生化研究表明，这些rRNA修饰刺激蛋白质合成。核糖体的冷冻电镜（cryo-EM）结构表明，这些缺氧诱导的修饰稳定了p位点和PTC。这些发现表明，在缺氧条件下，核糖体被缺氧诱导的修饰激活，以增强翻译能力，从而提高生存能力。
{"title":"Hypoxia-induced ribosomal RNA modifications in the peptidyl-transferase center contribute to anaerobic growth of bacteria","authors":"Kensuke Ishiguro, Karin Midorikawa, Naoki Shigi, Satoshi Kimura, Aivar Liiv, Takeshi Yokoyama, Takuhiro Ito, Mikako Shirouzu, Jaanus Remme, Kenjyo Miyauchi, Tsutomu Suzuki","doi":"10.1016/j.molcel.2025.11.018","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.018","url":null,"abstract":"Ribosomal RNAs (rRNAs) contain various modifications that play critical roles in ribosome assembly and function. Here, we discovered two stereoselective methylations of the rRNA backbone in the peptidyl-transferase center (PTC) of the 50S subunit of Escherichia coli cultured under anaerobic conditions. Methylation occurs at carbon 5'(S) of ribose moieties of dihydrouridine at position 2449 (D5Sm2449) and 2'-O-metylcytidine at position 2498 (Cm5Sm2498). We identified the rlmX gene, encoding a cobalamin-dependent radical S-adenosylmethionine (SAM) methyltransferase responsible for these methylations. Intriguingly, D5Sm2449, Cm5Sm2498, and 5-hydroxycytidine (ho5C2501) in the PTC were elevated under anaerobic growth conditions. A double knockout strain lacking rlmX and rlhA (responsible for ho5C2501) impaired anaerobic growth. Biochemical studies showed that these rRNA modifications stimulate protein synthesis. The cryoelectron microscopy (cryo-EM) structure of the ribosome indicated that these hypoxia-induced modifications stabilize the P-site and the PTC. These findings demonstrate that ribosomes are activated by hypoxia-induced modifications to enhance translational capability and thereby survival, under anaerobic conditions.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"13 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-10DOI: 10.1016/j.molcel.2025.11.017
Alfred M. Lentzsch, Ziyi Fan, Inayat U. Irshad, Edward P. O’Brien, Ajeet K. Sharma, Rachel Green, Shu-ou Shan
Numerous protein biogenesis factors cotranslationally facilitate the maturation of nascent proteins. Among them, N-terminal acetyltransferase A (NatA) acetylates the N terminus of ∼40% of the eukaryotic proteome. NatA is bound to Huntingtin-interacting protein K (HYPK), which inhibits NatA activity in vitro but enhances function in vivo. Here, kinetic and in-cell measurements resolve this paradox, showing that HYPK acts as a ribosome exchange factor for NatA. Without HYPK, hyper-tight ribosome binding prevents NatA from accessing additional ribosomes following each round of acetylation. HYPK accelerates NatA dissociation from the ribosome to license multiple turnovers, allowing a sub-stoichiometric level of this enzyme to globally acetylate the nascent proteome. Our results uncover a previously unidentified function of HYPK and demonstrate that a "Goldilocks" zone of ribosome interaction kinetics is required for cotranslational protein biogenesis machineries to act on all translating ribosomes in the cell.
{"title":"HYPK promotes N-terminal protein acetylation through rapid ribosome exchange of NatA","authors":"Alfred M. Lentzsch, Ziyi Fan, Inayat U. Irshad, Edward P. O’Brien, Ajeet K. Sharma, Rachel Green, Shu-ou Shan","doi":"10.1016/j.molcel.2025.11.017","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.017","url":null,"abstract":"Numerous protein biogenesis factors cotranslationally facilitate the maturation of nascent proteins. Among them, N-terminal acetyltransferase A (NatA) acetylates the N terminus of ∼40% of the eukaryotic proteome. NatA is bound to Huntingtin-interacting protein K (HYPK), which inhibits NatA activity in vitro but enhances function in vivo. Here, kinetic and in-cell measurements resolve this paradox, showing that HYPK acts as a ribosome exchange factor for NatA. Without HYPK, hyper-tight ribosome binding prevents NatA from accessing additional ribosomes following each round of acetylation. HYPK accelerates NatA dissociation from the ribosome to license multiple turnovers, allowing a sub-stoichiometric level of this enzyme to globally acetylate the nascent proteome. Our results uncover a previously unidentified function of HYPK and demonstrate that a \"Goldilocks\" zone of ribosome interaction kinetics is required for cotranslational protein biogenesis machineries to act on all translating ribosomes in the cell.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"1 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-09DOI: 10.1016/j.molcel.2025.11.014
Wenqiang Zheng, Tatsuya Hagino, Hao Wang, Henry Yi Cheng, Nicholas Koylass, Kevin Hong Chen, Haobo Wang, Sepehr Mani, Anish Kumar Mondal, Edward C. Twomey, Zhaozhu Qiu
Volume-regulated anion channels (VRACs) are large-pore channels expressed in most vertebrate cells and are critical for cell volume regulation and autocrine/paracrine signaling. Here, we identify the ubiquitously expressed puromycin-sensitive aminopeptidase (PSA) as a binding partner of the obligatory VRAC subunit SWELL1 (also known as LRRC8A) and determine the cryo-electron microscopy structure of the SWELL1-PSA complex. Three PSA molecules bind a single SWELL1 hexamer, coupling adjacent leucine-rich repeat (LRR) domains into local dimers. Functionally, PSA overexpression suppresses VRAC activation, whereas PSA deletion dramatically elevates basal channel activity. Notably, PSA’s modulation of VRACs requires physical binding but not aminopeptidase activity, indicating a structural mechanism. Our findings identify PSA as an auxiliary subunit of VRACs, highlight the role of intracellular LRR domains in allosteric channel gating, and suggest a strategy to tune VRAC function in diverse physiological contexts, including 2′3′-cyclic GMP-AMP (cGAMP) transport and downstream stimulator of interferon genes (STING) signaling.
{"title":"Puromycin-sensitive aminopeptidase acts as an inhibitory auxiliary subunit of volume-regulated anion channels and regulates cGAMP transport","authors":"Wenqiang Zheng, Tatsuya Hagino, Hao Wang, Henry Yi Cheng, Nicholas Koylass, Kevin Hong Chen, Haobo Wang, Sepehr Mani, Anish Kumar Mondal, Edward C. Twomey, Zhaozhu Qiu","doi":"10.1016/j.molcel.2025.11.014","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.014","url":null,"abstract":"Volume-regulated anion channels (VRACs) are large-pore channels expressed in most vertebrate cells and are critical for cell volume regulation and autocrine/paracrine signaling. Here, we identify the ubiquitously expressed puromycin-sensitive aminopeptidase (PSA) as a binding partner of the obligatory VRAC subunit SWELL1 (also known as LRRC8A) and determine the cryo-electron microscopy structure of the SWELL1-PSA complex. Three PSA molecules bind a single SWELL1 hexamer, coupling adjacent leucine-rich repeat (LRR) domains into local dimers. Functionally, PSA overexpression suppresses VRAC activation, whereas PSA deletion dramatically elevates basal channel activity. Notably, PSA’s modulation of VRACs requires physical binding but not aminopeptidase activity, indicating a structural mechanism. Our findings identify PSA as an auxiliary subunit of VRACs, highlight the role of intracellular LRR domains in allosteric channel gating, and suggest a strategy to tune VRAC function in diverse physiological contexts, including 2′3′-cyclic GMP-AMP (cGAMP) transport and downstream stimulator of interferon genes (STING) signaling.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"1 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-09DOI: 10.1016/j.molcel.2025.11.015
Kailey Worner, Katharine R. Maschhoff, Gabrielle M. Schuh, Wenqian Hu
Controlling mRNA translation is critical for proper protein production. Although translation initiation and elongation regulations are becoming increasingly clear, whether and how translation termination is monitored remains poorly understood. Using an acute protein degradation system coupled with phenotypic rescue via ectopic expression, here we show that the impaired translation termination reaction leads to the rapid activation of GCN2, resulting in eIF2α phosphorylation and inhibition of translation initiation, which occurs prior to ribosome collisions. Ribosome profiling analyses reveal that GCN2 monitors terminating ribosomes and prevents ribosome collisions and translation readthrough when translation termination is compromised. This rapid activation of GCN2 by compromised translation termination occurs in both stem and somatic cells and in mouse and human cells. These results suggest a conserved surveillance mechanism for translation termination.
{"title":"GCN2 monitors mRNA translation termination","authors":"Kailey Worner, Katharine R. Maschhoff, Gabrielle M. Schuh, Wenqian Hu","doi":"10.1016/j.molcel.2025.11.015","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.015","url":null,"abstract":"Controlling mRNA translation is critical for proper protein production. Although translation initiation and elongation regulations are becoming increasingly clear, whether and how translation termination is monitored remains poorly understood. Using an acute protein degradation system coupled with phenotypic rescue via ectopic expression, here we show that the impaired translation termination reaction leads to the rapid activation of GCN2, resulting in eIF2α phosphorylation and inhibition of translation initiation, which occurs prior to ribosome collisions. Ribosome profiling analyses reveal that GCN2 monitors terminating ribosomes and prevents ribosome collisions and translation readthrough when translation termination is compromised. This rapid activation of GCN2 by compromised translation termination occurs in both stem and somatic cells and in mouse and human cells. These results suggest a conserved surveillance mechanism for translation termination.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"5 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1016/j.molcel.2025.11.007
Meichen Wang, Hai-Qiang Dai
Conventional methods have failed to simultaneously integrate one-dimensional transcriptional studies with three-dimensional chromatin architecture. In this issue, Li et al.1 present Hi-Coatis, an antibody- and probe-free approach that seamlessly maps active transcription-associated chromatin networks with high sensitivity and spatial resolution.
{"title":"Hi-Coatis: Capturing the 3D interplay between transcription and chromatin architecture","authors":"Meichen Wang, Hai-Qiang Dai","doi":"10.1016/j.molcel.2025.11.007","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.007","url":null,"abstract":"Conventional methods have failed to simultaneously integrate one-dimensional transcriptional studies with three-dimensional chromatin architecture. In this issue, Li et al.<span><span><sup>1</sup></span></span> present Hi-Coatis, an antibody- and probe-free approach that seamlessly maps active transcription-associated chromatin networks with high sensitivity and spatial resolution.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"1 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1016/j.molcel.2025.11.001
Roman Barth, Richard Janissen, Laura Muras, Jaco van der Torre, Gabriele Litos, Eli van der Sluis, Ashmiani van den Berg, Iain F. Davidson, Jan-Michael Peters, Cees Dekker
Human cohesin extrudes DNA into loops and is positioned along the genome by stalling at the human CCCTC-binding factor (CTCF) upon encountering its N-terminal region (NTR). The mechanism underlying this stalling, however, is unresolved. Using single-molecule assays that monitor DNA loop extrusion (LE) in the presence of NTR fragments, we identify two amino acid motifs, YDF and KTYQR, which hinder LE. KTYQR is found to completely block LE activity, while YDF hinders cohesin from completing LE step cycles and converts cohesin into a unidirectional extruder by strengthening the affinity of STAG1 to DNA. We thus identify two distinct NTR motifs that stall LE via different yet synergistic mechanisms, highlighting the multifaceted ways employed by CTCF to modulate LE to shape and regulate genomes.
{"title":"Two CTCF motifs impede cohesin-mediated DNA loop extrusion","authors":"Roman Barth, Richard Janissen, Laura Muras, Jaco van der Torre, Gabriele Litos, Eli van der Sluis, Ashmiani van den Berg, Iain F. Davidson, Jan-Michael Peters, Cees Dekker","doi":"10.1016/j.molcel.2025.11.001","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.001","url":null,"abstract":"Human cohesin extrudes DNA into loops and is positioned along the genome by stalling at the human CCCTC-binding factor (CTCF) upon encountering its N-terminal region (NTR). The mechanism underlying this stalling, however, is unresolved. Using single-molecule assays that monitor DNA loop extrusion (LE) in the presence of NTR fragments, we identify two amino acid motifs, YDF and KTYQR, which hinder LE. KTYQR is found to completely block LE activity, while YDF hinders cohesin from completing LE step cycles and converts cohesin into a unidirectional extruder by strengthening the affinity of STAG1 to DNA. We thus identify two distinct NTR motifs that stall LE via different yet synergistic mechanisms, highlighting the multifaceted ways employed by CTCF to modulate LE to shape and regulate genomes.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"13 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1016/j.molcel.2025.11.005
Anouk P Jurgens, Josephine Zwijnen, Antonia Bradarić, Floris P J van Alphen, Kaspar Bresser, Koos Rooijers, Arie J Hoogendijk, Branka Popović, Monika C Wolkers
T cells are key contributors to clearing our body of infected and malignant cells. During activation, T cells undergo profound translational alterations, and the evolutionarily and highly conserved kinase mammalian target of rapamycin (mTOR) is central in this process. It mediates T cell differentiation, homeostasis, and activation and promotes the production of pro-inflammatory cytokines. mTOR executes its translation activity through terminal oligopyrimidine (TOP) motifs located in the 5' untranslated region (5' UTR) of target genes. Here, we uncovered a distinct 3' UTR-mediated mechanism of mTOR signaling on cytokine production in T cells. Non-classical TOP motifs present in the cytokine 3' UTRs do not contribute to mTOR-mediated translation regulation. Rather, AU-rich elements (AREs) are required for mTOR-mediated cytokine production. Furthermore, we discovered that the RNA-binding protein DDX21 binds to 3' UTR AREs and confers mTOR-mediated translation control. In conclusion, we present a previously unappreciated ARE-dependent, 3' UTR-mediated mechanism that mTOR employs to regulate cytokine production.
{"title":"mTOR signaling during T cell activation promotes cytokine production in T cells through 3' UTR-mediated translation control.","authors":"Anouk P Jurgens, Josephine Zwijnen, Antonia Bradarić, Floris P J van Alphen, Kaspar Bresser, Koos Rooijers, Arie J Hoogendijk, Branka Popović, Monika C Wolkers","doi":"10.1016/j.molcel.2025.11.005","DOIUrl":"https://doi.org/10.1016/j.molcel.2025.11.005","url":null,"abstract":"<p><p>T cells are key contributors to clearing our body of infected and malignant cells. During activation, T cells undergo profound translational alterations, and the evolutionarily and highly conserved kinase mammalian target of rapamycin (mTOR) is central in this process. It mediates T cell differentiation, homeostasis, and activation and promotes the production of pro-inflammatory cytokines. mTOR executes its translation activity through terminal oligopyrimidine (TOP) motifs located in the 5' untranslated region (5' UTR) of target genes. Here, we uncovered a distinct 3' UTR-mediated mechanism of mTOR signaling on cytokine production in T cells. Non-classical TOP motifs present in the cytokine 3' UTRs do not contribute to mTOR-mediated translation regulation. Rather, AU-rich elements (AREs) are required for mTOR-mediated cytokine production. Furthermore, we discovered that the RNA-binding protein DDX21 binds to 3' UTR AREs and confers mTOR-mediated translation control. In conclusion, we present a previously unappreciated ARE-dependent, 3' UTR-mediated mechanism that mTOR employs to regulate cytokine production.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"85 23","pages":"4452-4462.e5"},"PeriodicalIF":16.6,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：