Nature Cell Biology最新文献

{"title":"Nuclear mechanics as a determinant of nuclear pore complex plasticity","authors":"C. Patrick Lusk, Kimberly J. Morgan, Megan C. King","doi":"10.1038/s41556-025-01768-w","DOIUrl":"10.1038/s41556-025-01768-w","url":null,"abstract":"Thousands of nuclear pore complexes (NPCs) cover the nuclear surface of mammalian cells and establish selective transport conduits that biochemically segregate the nucleoplasm and cytoplasm. Although the molecular composition and structure of archetypical NPCs are well understood, distinct NPCs composed of varying nucleoporins exist in different cell types and even within individual cells. Furthermore, the integration of NPCs within mechanosensitive networks impacts their dilation state. However, whether (and how) the dilation or compositional plasticity of NPCs impacts their primary role as selective transport channels remains unclear. Based on our current understanding of NPC plasticity, we propose here that nuclear membrane tension and the resulting dilation of nuclear pores is a determinant of the compositional plasticity of NPCs, thus providing a framework to interpret how nucleoporins may influence cell fate decisions and explain the tissue-specificity of some NPC-related diseases. In this Review, Lusk et al. discuss emerging insights into nuclear pore complex variability with regard to composition and dilation state, and propose nuclear mechanics as a key determinant of driving such plasticity and any associated diseases.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1622-1631"},"PeriodicalIF":19.1,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089750","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}

{"title":"A subset of transposable elements as mechano-response enhancer elements in controlling human embryonic stem cell fate","authors":"Tongyu Sun, Yueyuan Xu, Nicole Angel, Luna Chen, Kan Zhang, Brenton D. Hoffman, Jianhong Ou, Zhipeng Meng, Shyni Varghese, Yarui Diao","doi":"10.1038/s41556-025-01770-2","DOIUrl":"10.1038/s41556-025-01770-2","url":null,"abstract":"Transposable elements (TEs), constituting half of the human genome, are essential for development and diseases. While the regulation of TE activity by cellular intrinsic mechanisms is well documented, their response to microenvironmental signals, particularly mechanical cues involving numerous biological processes, remains unknown. Here we show that various TE families, notably LTR7, undergo transcriptomic, epigenetic and three-dimensional genome changes in response to matrix mechanical cues in human embryonic stem cells. Interestingly, LTR7s act as ‘mechano-response enhancer elements’ (MREEs), controlling the gene expression and cell fate of human embryonic stem cells. Mechanistically, mechano-effectors YAP/TEAD1 control LTR7’s epigenetic activity by engaging with BRD4. Furthermore, YAP recruits CTCF, a key genome architecture protein, to facilitate long-range interactions between gene promoters and TEs as MREEs. In particular, a mechano-responsive LTR7 element is a distal enhancer for FAM189A2, thereby inhibiting definitive endoderm differentiation. These findings highlight the underappreciated role of TEs as MREEs that control human cell fate and gene expression. Sun et al. identify a subset of transposable elements that serve as mechano-response enhancer elements that control gene expression and human stem cell fate.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1785-1796"},"PeriodicalIF":19.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078228","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}

{"title":"Two microbiome metabolites compete for tRNA modification to impact mammalian cell proliferation and translation quality control","authors":"Wen Zhang, Kuldeep Lahry, Denis Cipurko, Sihao Huang, Olivia Zbihley, Amanda M. Sevilleja, Dominika Rudzka, Luke R. Frietze, Mahdi Assari, Christopher D. Katanski, Marisha Singh, Aurore Attina, Hélène Guillorit, Christopher P. Watkins, Delphine Gourlain, Didier Varlet, Jennifer Falconi, Alexandre Djiane, Christophe Hirtz, Hankui Chen, Françoise Macari, Katherine Johnson, Nicolas Chevrier, Alexandre David, Tao Pan","doi":"10.1038/s41556-025-01750-6","DOIUrl":"10.1038/s41556-025-01750-6","url":null,"abstract":"The microbiome affects eukaryotic host cells via many metabolites, including the well-studied queuine as substrate for host tRNA queuosine modification. The microbial metabolite pre-queuosine 1 (preQ1) is produced in the bacterial tRNA queuosine biosynthesis pathway, with unknown effects on host cell biology. Here we show that preQ1 strongly represses cell proliferation in both human and mouse cells. Queuine reverses this effect by competing with preQ1 to modify the same tRNA. PreQ1 is detectable in the plasma and tissues of mice, and its injection suppresses tumour growth in a mouse cancer model. Mechanistically, preQ1 reduces cognate tRNA levels specifically, as well as codon-dependent translation of housekeeping genes. We identify the endoplasmic reticulum-localized inositol-requiring enzyme 1 (IRE1) ribonuclease as the enzyme responsible for the selective degradation of preQ1-modified tRNAs on translating ribosomes. Our results identify two microbial metabolites competing for host tRNA modification, which elicits translation quality control and impacts cell proliferation. Zhang, Lahry, Cipurko et al. show that the microbial metabolites queuine and preQ1 modify the same host tRNA. PreQ1-tRNA reduces cell proliferation, slows tumour growth, decreases the translation of ribosomal proteins and is cleaved by IRE1 on the ER ribosome.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1812-1826"},"PeriodicalIF":19.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067760","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}

{"title":"Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer","authors":"Taslim A. Al-Hilal, Maria-Anna Chrysovergi, Paula E. Grasberger, Fei Liu, Vera Auernheimer, Yan Zhou, Zebin Xiao, Mark Anthony Leon-Duque, Alba Santos, Tamanna Islam, Matteo Ligorio, Delphine Sicard, Clemens K. Probst, Vladimir Vrbanac, Tejaswini S. Reddi, Ludovic Vincent, Cassandra Happe, Edward Chaum, Charles R. Yates, Kaveh Daneshvar, Allan C. Mullen, David Ting, Eric S. White, Raghu Kalluri, Christina M. Woo, Ellen Puré, Wolfgang H. Goldmann, Jose Luis Alonso, Andrew M. Tager, Adam J. Engler, Daniel J. Tschumperlin, David Lagares","doi":"10.1038/s41556-025-01697-8","DOIUrl":"10.1038/s41556-025-01697-8","url":null,"abstract":"Durotaxis, cell migration along stiffness gradients, is linked to embryonic development, tissue repair and disease. Despite solid in vitro evidence, its role in vivo remains largely speculative. Here we demonstrate that durotaxis actively drives disease progression in vivo in mouse models of lung fibrosis and metastatic pancreatic cancer. In lung fibrosis, durotaxis directs fibroblast recruitment to sites of injury, where they undergo mechano-activation into scar-forming myofibroblasts. In pancreatic cancer, stiffening of the tumour microenvironment induces durotaxis of cancer cells, promoting metastatic dissemination. Mechanistically, durotaxis is mediated by focal adhesion kinase (FAK)–paxillin interaction, a mechanosensory module that links stiffness cues to transcriptional programmes via YAP signalling. To probe this genetically, we generated a FAK-FATL994E knock-in mouse, which disrupts FAK–paxillin binding, blocks durotaxis and attenuates disease severity. Pharmacological inhibition of FAK–paxillin interaction with the small molecule JP-153 mimics these effects. Our findings establish durotaxis as a disease mechanism in vivo and support anti-durotactic therapy as a potential strategy for treating fibrosis and cancer. Al-Hilal, Chrysovergi et al. identify a role for durotaxis in lung fibrosis and metastatic pancreatic cancer, mediated by the FAK–paxillin mechanosensor complex, and demonstrate therapeutic targeting of this pathway using the small molecule JP-153.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 9","pages":"1543-1554"},"PeriodicalIF":19.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01697-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD160+CD8+ T cells for improved immunotherapy","authors":"Yi-Hao Wang, Stanislav Dergun, Ping-Chih Ho","doi":"10.1038/s41556-025-01756-0","DOIUrl":"10.1038/s41556-025-01756-0","url":null,"abstract":"A study now indicates that CD160⁺CD8⁺ T cells in patients with colorectal cancer modulate anti-tumour immune responses and may influence disease progression. Their combination with immune checkpoint blockade therapy has emerged as a promising strategy to enhance therapeutic efficacy and patient outcomes in colorectal cancer.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 9","pages":"1389-1390"},"PeriodicalIF":19.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017319","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}

{"title":"CD160 dictates anti-PD-1 immunotherapy resistance by regulating CD8+ T cell exhaustion in colorectal cancer","authors":"Tongsen Zheng, Chujie Ding, Shihui Lai, Yang Gao, Cheng Lyu, Caiqi Liu, Jiaqi Shi, Xiaobo Li, Mingwei Li, Hongxue Meng, Mingqi Li, Yingjian Liang, Sheng Tai, Liang Cheng, Yan Zhang, Li Li, Peng Han, Bin Sun, Te Liu, Feng Geng, Dapeng Hao, Xue Zhang","doi":"10.1038/s41556-025-01753-3","DOIUrl":"10.1038/s41556-025-01753-3","url":null,"abstract":"The colon exhibits higher propensity for tumour development than ileum. However, the role of immune microenvironment differences in driving this disparity remains unclear. Here, by comparing paired ileum and colon samples from patients with colorectal cancer (CRC) and healthy donors, we identified ileum-enriched CD160+CD8+ T cells with previously unrecognized characteristics, including resistance to terminal exhaustion and strong clonal expansion. The transfer of CD160+CD8+ T cells significantly inhibits tumour growth in microsatellite instability-high and inflammation-induced CRC models. Cd160 knockout accelerates tumour growth, which is mitigated by transferring CD160+CD8+ T cells. Notably, in microsatellite instability-high and anti-PD-1-resistant CRC models, CD160+CD8+ T cells improve anti-PD-1 efficacy and overcome its resistance by increasing tumour-infiltrating progenitor-exhausted T cells, nearly eradicating tumours. Mechanistically, we uncover a CD160–PI3K (p85α) interaction that promotes FcεR1γ and 4-1BB expression via the AKT–NF-κB pathway, thereby enhancing CD8+ T cell cytotoxicity. Our study reveals CD160 as a crucial regulator of CD8+ T cell function and proposes an innovative immunotherapy strategy of transferring CD160+CD8+ T cells to overcome anti-PD-1 resistance. Zheng et al. identify a role for CD160 in regulating CD8+ T cell exhaustion and cytotoxicity through the AKT–NF-κB pathway. The transfer of CD160+CD8+ T cells overcomes resistance to anti-PD-1 treatment in colorectal cancer models.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 9","pages":"1555-1571"},"PeriodicalIF":19.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017320","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}

{"title":"RNA-binding proteins pull in chromatin loops","authors":"Ann Dean","doi":"10.1038/s41556-025-01743-5","DOIUrl":"10.1038/s41556-025-01743-5","url":null,"abstract":"During development as cells exit a pluripotent state, chromatin looping interactions are strengthened, but the mechanism for this is unknown. A study now shows that CTCF–RBP interactions increase upon differentiation of embryonic stem cells to neural stem cells, and that the non-coding RNA Pantr1 collaborates with CTCF and RBPs to contract the genome.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 9","pages":"1387-1388"},"PeriodicalIF":19.1,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009056","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}

{"title":"Hbo1 and Msl complexes preserve differential compaction and H3K27me3 marking of active and inactive X chromosomes during mitosis","authors":"Dounia Djeghloul, Sherry Cheriyamkunnel, Bhavik Patel, Holger Kramer, Alex Montoya, Karen E. Brown, Chad Whilding, Tatyana B. Nesterova, Guifeng Wei, Neil Brockdorff, Iga Grządzielewska, Remzi Karayol, Asifa Akhtar, Matthias Merkenschlager, Amanda G. Fisher","doi":"10.1038/s41556-025-01748-0","DOIUrl":"10.1038/s41556-025-01748-0","url":null,"abstract":"In mammals, chromosome-wide regulatory mechanisms ensure a balance of X-linked gene dosage between males (XY) and females (XX). In female cells, expression of genes from one of the two X chromosomes is curtailed, with selective accumulation of Xist-RNA, Xist-associated proteins, specific histone modifications (for example, H3K27me3) and Barr body formation observed throughout interphase. Here we show, using chromosome flow-sorting, that during mitosis, Xist-associated proteins dissociate from inactive X (Xi) chromosomes, while high levels of H3K27me3 and increased compaction of the Xi relative to active X (Xa), are retained. Proteomic comparison of mitotic Xi and Xa revealed that components of Hbo1 and Msl/Mof histone acetyltransferase complexes are significantly enriched on Xa as compared to Xi and autosomes. By contrast, inhibitors of histone acetylation co-enrich with Xi. Furthermore, inhibition of Hbo1 or deletion of Msl/Mof components functionally abolishes mitotic differences in H3K27me3 marking and chromosome compaction. These data uncover critical roles for acetylation pathways in preserving X chromosome properties during mitosis. Djeghloul, Cheriyamkunnel et al. apply chromosome sorting to isolate active and inactive X chromosomes and report a role for Hbo1 and Msl histone acetyltransferase complexes in preserving active X chromosomes in female cells during mitosis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 9","pages":"1482-1495"},"PeriodicalIF":19.1,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01748-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA-binding proteins mediate the maturation of chromatin topology during differentiation","authors":"Bondita Dehingia, Małgorzata Milewska-Puchała, Marcin Janowski, Mahmoud-Reza Rafiee, Misbah Abbas, Aleksandra Piotrowska, Jan Senge, Piotr Blaut, Dietrich Walsh, Jacqueline Severino, Debadeep Chaudhury, Sajjad Iqbal, Rogelio Montiel-Manriquez, Sylwia Jankowska, Peyman Zare, Wolfgang Huber, Jianliang Xu, Rafael Casellas, Timo Zimmermann, Paweł Dłotko, Jeroen Krijgsveld, Aleksandra Pękowska","doi":"10.1038/s41556-025-01735-5","DOIUrl":"10.1038/s41556-025-01735-5","url":null,"abstract":"Topologically associating domains (TADs) and chromatin architectural loops impact promoter–enhancer interactions, with CCCTC-binding factor (CTCF) defining TAD borders and loop anchors. TAD boundaries and loops progressively strengthen upon embryonic stem (ES) cell differentiation, underscoring the importance of chromatin topology in ontogeny. However, the mechanisms driving this process remain unclear. Here we show a widespread increase in CTCF–RNA-binding protein (RBP) interactions upon ES to neural stem (NS) cell differentiation. While dispensable in ES cells, RBPs reinforce CTCF-anchored chromatin topology in NS cells. We identify Pantr1, a non-coding RNA, as a key facilitator of CTCF–RBP interactions, promoting chromatin maturation. Using acute CTCF degradation, we find that, through its insulator function, CTCF helps maintain neuronal gene silencing in NS cells by acting as a barrier to untimely gene activation during development. Altogether, we reveal a fundamental mechanism driving developmentally linked chromatin structural consolidation and the contribution of this process to the control of gene expression in differentiation. Dehingia, Milewska-Puchała and colleagues find a pervasive lncRNA-mediated increase in interactions between CTCF and RNA-binding proteins during embryonic stem cell differentiation. These interactions reinforce chromatin architecture in neural cells.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 9","pages":"1510-1525"},"PeriodicalIF":19.1,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01735-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fusion oncoproteins acquire condensate propensity to initiate tumour formation","authors":"","doi":"10.1038/s41556-025-01746-2","DOIUrl":"10.1038/s41556-025-01746-2","url":null,"abstract":"Gene fusions are potent drivers of cancer, and nuclear condensates are known to have a role in transcription. By creating synthetic fusion oncogenes, we show that nuclear condensate formation might be a general feature of fusion oncoprotein-directed transcription, including in brain tumour development.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 9","pages":"1396-1397"},"PeriodicalIF":19.1,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995785","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}