Nature Cell Biology最新文献

{"title":"Mosaic gastruloids reveal a temporal restriction for developmental cell competition.","authors":"Joshua D Frenster,Stephen Babin,Pablo Casani-Galdon,Joel B Josende-Garcia,Pau Pascual-Mas,Gaëlle Robertson,Shlomit Edri,Alexandra E Wehmeyer,Sebastian J Arnold,Jordi Garcia Ojalvo,Alfonso Martinez Arias","doi":"10.1038/s41556-026-01923-x","DOIUrl":"https://doi.org/10.1038/s41556-026-01923-x","url":null,"abstract":"Selective elimination of suboptimal cells is critical for the developmental integrity of early mammalian embryogenesis. Cell competition is a non-autonomous quality control in which 'winner' cells outcompete viable but suboptimal 'loser' cells based on fitness differences. Here we investigate cell competition dynamics using mosaic mouse gastruloids, a 3D embryonic stem cell-based model of gastrulation. Introducing just two Trp53-deficient supercompetitor cells suffices to impair growth in neighbouring wild-type cells through mitochondrial apoptosis. Competition is tightly restricted to a developmental transition stage between primed pluripotency and early gastrulation and involves gene regulatory networks of pluripotency exit. Heterochronic gastruloids from developmental stage-shifted cells, EpiGastruloids, and dynamic p53-degrons reveal that both winners and losers must reside within this permissive stage, during which acute relative p53 protein levels determine competitive outcomes. These findings advance our understanding of cell fitness evaluation and establish gastruloids as a powerful 3D model for investigating developmental stage-specific cell competition in mammalian embryogenesis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147585750","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":"Reinvigorating COTL1high NK cells via GITR signalling overcomes immune checkpoint blockade resistance in tsMHC-I-impaired tumours.","authors":"Wenhua You,Chupeng Hu,Yuhan Zhang,Yedi Huang,Jianzhou Yuan,Cai-Yuan Wu,Deyuan Kong,Mengya Zhao,Yueqing Han,Songmao Li,Ruimin Shan,Jinying Lu,Ming Cheng,Qing Li,Bin Yao,Xiao-Fang Yu,Qing Xia,Wei Chong,Dong-Ming Kuang,Yun Chen","doi":"10.1038/s41556-026-01925-9","DOIUrl":"https://doi.org/10.1038/s41556-026-01925-9","url":null,"abstract":"Patients with impaired tumour-specific major histocompatibility complex class I (tsMHC-Iimpaired) often fail to respond to immune checkpoint blockade (ICB), presenting a major clinical challenge. However, through our multicentre investigation, we observed that a subset of patients with tsMHC-Iimpaired remains responsive to ICB, a phenomenon that has not been fully explained. Here we identify a COTL1high natural killer (NK) subset that mediates ICB responsiveness in these patients. Mechanistically, PD-L1+ macrophages coexpress GITRL and engage GITR on COTL1high NK cells, whereas PD-L1 blockade relieves the PD-1-mediated inhibition of GITR signalling and promotes NK cell activation. Activated COTL1high NK cells enhance immunological synapse stability and IFN-γ production via a metabolic-H3K27ac-RBPJ axis, thereby upregulating tsMHC-I expression and reinforcing adaptive anti-tumour immunity. Notably, GITR activation significantly enhances the sensitivity to anti-PD-L1 therapy in tsMHC-Iimpaired models. Our findings identify COTL1high NK cells as key determinants of ICB responsiveness and highlight the GITRL-GITR axis as a promising therapeutic target for tsMHC-Iimpaired tumours.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"62 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147578347","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":"Linking TDP-43-regulated paraspeckle condensation to neuroprotection","authors":"","doi":"10.1038/s41556-026-01932-w","DOIUrl":"10.1038/s41556-026-01932-w","url":null,"abstract":"Paraspeckle condensates are membraneless nuclear organelles linked to stress responses and disease states. We demonstrate that paraspeckle assembly is tightly controlled by antagonism between TDP-43 and other paraspeckle proteins, through non-random distribution of TDP-43 binding sites on the scaffolding RNA NEAT1. Structural changes in NEAT1 or altered protein stoichiometry affect condensate formation, with implications for neurodegeneration.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 4","pages":"657-658"},"PeriodicalIF":19.1,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147578345","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":"An EGFR co-amplified lncRNA HELDR promotes glioblastoma malignancy through KAT7-driven gene programs.","authors":"Xiaozhou Yu,Xiao Song,Richard A Schäfer,Qingshu Meng,Deanna Tiek,Runxin Wu,Qiu He,Maya Walker,Qi Cao,Rendong Yang,Bo Hu,Shi-Yuan Cheng","doi":"10.1038/s41556-026-01924-w","DOIUrl":"https://doi.org/10.1038/s41556-026-01924-w","url":null,"abstract":"EGFR amplification frequently occurs within extrachromosomal DNAs (ecDNAs) and is the most prevalent mutation in glioblastoma (GBM). However, targeting EGFR for GBM treatments has been unsuccessful. Here we show a long non-coding RNA (lncRNA) that is co-amplified with EGFR, which we name hidden EGFR long non-coding downstream RNA (HELDR). HELDR is a GBM-selective lncRNA that promotes tumorigenicity independent of EGFR signalling. HELDR exhibits widespread chromatin association and recruits the transcription co-activator p300 to the KAT7 promoter. p300-induced H3K27ac at the KAT7 promoter enlists other co-transcription factors, activating KAT7 transcription. KAT7 induces H3K14ac and H4K12ac that activate KAT7-driven gene programmes that are critical for GBM malignancy. Targeting KAT7 or HELDR markedly enhances therapeutic effects of anti-EGFR treatments for GBM. These results not only reveal the role of HELDR in EGFR-amplified GBM but also provide a strong rationale to characterize the role of lncRNAs co-amplified with driver oncogenes in human cancers.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"58 1 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147524399","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":"Active size control of condensates by a kinase-based mechanism","authors":"","doi":"10.1038/s41556-026-01917-9","DOIUrl":"10.1038/s41556-026-01917-9","url":null,"abstract":"How cells actively control the size of biomolecular condensates to facilitate biological processes remains poorly understood. We show that in the pyrenoid — a biomolecular condensate that mediates approximately one-third of global CO2 fixation in algae — the kinase KEY1 disrupts phase-separation interactions to dynamically control the condensate size setpoint across the cell cycle.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 4","pages":"655-656"},"PeriodicalIF":19.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506818","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":"Nonsense-mediated mRNA decay safeguards telomeres in pluripotent stem cells","authors":"Marta Markiewicz-Potoczny, Si Young Lee, Soniya Chatterjee, Justin W. Mabin, Anna Zinsser, Ranjodh Sandhu, Gianna Tricola, J. Robert Hogg, Eros Lazzerini Denchi","doi":"10.1038/s41556-026-01912-0","DOIUrl":"10.1038/s41556-026-01912-0","url":null,"abstract":"Telomeres are protective DNA caps at chromosome ends that prevent cells from mistakenly recognizing them as broken DNA. These structures are safeguarded by a protein complex called Shelterin, particularly through the TRF2 protein encoded by Trf2. Surprisingly, in mouse embryonic stem cells, TRF2 is not essential for telomere protection, suggesting that other mechanisms compensate for its loss. Here we show that a cellular quality control system called nonsense-mediated mRNA decay (NMD), which normally eliminates defective RNA molecules, plays an unexpected role in maintaining telomere integrity in pluripotent cells. Through a genome-wide genetic screen, we discovered that NMD is essential for cell survival when TRF2 is absent. NMD accomplishes this by degrading an aberrant form of the messenger RNA encoded by Trf1, which produces the TRF1 protein, another Shelterin component. Without NMD, this aberrant RNA produces a truncated, harmful version of TRF1 that interferes with normal telomere protection. Our findings reveal that embryonic stem cells use a unique strategy for chromosome end protection, linking RNA quality control to genome stability in a previously unrecognized way. Markiewicz-Potoczny et al. report that the nonsense-mediated mRNA decay pathway protects telomeres in the absence of core Shelterin component TRF2 by regulating the stability and abundance of TRF1 at telomeres.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 4","pages":"674-683"},"PeriodicalIF":19.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-026-01912-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506144","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":"Visualizing suborganellar lipid distribution using correlative light and electron microscopy","authors":"H. Mathilda Lennartz, Suman Khan, Weihua Leng, Kristin Böhlig, Gunar Fabig, Yannick Kieswald, Falk Elsner, Nadav Scher, Michaela Wilsch-Bräuninger, Ori Avinoam, André Nadler","doi":"10.1038/s41556-026-01915-x","DOIUrl":"10.1038/s41556-026-01915-x","url":null,"abstract":"Lipids and proteins compartmentalize biological membranes into nanoscale domains, which are crucial for signalling, intracellular trafficking and many other cellular processes. Studying nanodomain function requires the ability to measure protein and lipid localization at the nanoscale. Current methods for visualizing lipid localization do not meet this requirement. Here we introduce a correlative light and electron microscopy workflow to image lipids (Lipid-CLEM), combining near-native lipid probes and on-section labelling by click chemistry. This approach enables the quantification of relative lipid densities in membrane nanodomains. We find differential partitioning of sphingomyelin into intraluminal vesicles, recycling tubules and the boundary membrane of the early endosome, representing a degree of nanoscale organization previously observed only for proteins. We anticipate that our Lipid-CLEM workflow will greatly facilitate the mechanistic analysis of lipid functions in cell biology, allowing for the simultaneous investigation of proteins and lipids during membrane nanodomain assembly and function. Lennartz et al. introduce a correlative light and electron microscopy workflow, Lipid-CLEM, combining near-native lipid probes and on-section labelling via click chemistry. Lipid-CLEM quantitatively analyses lipids in membrane nanodomains.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 4","pages":"828-837"},"PeriodicalIF":19.1,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-026-01915-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147491476","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":"Seeing lipids where they live","authors":"Aubrey Weigel","doi":"10.1038/s41556-026-01919-7","DOIUrl":"10.1038/s41556-026-01919-7","url":null,"abstract":"A study establishes a correlative light and electron microscopy workflow that reveals how individual lipid species distribute across nanoscale membrane domains, uncovering sphingomyelin sorting within the early endosome.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 4","pages":"653-654"},"PeriodicalIF":19.1,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147491473","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":"Paraspeckle condensation is controlled via TDP-43 polymerization and linked to neuroprotection","authors":"Rachel E. Hodgson, Wan-Ping Huang, Ruaridh Lang, Vedanth Kumar, Haiyan An, Emil G. P. Stender, Zhaklin P. Chalakova, Mark D. Driver, Anna Sanchez Avila, Brittany C. S. Ellis, Emily Day, Jessica A. Rayment, Kyungmin Baeg, Andrew Strange, Tobias Moll, Gareth S. A. Wright, Joke J. F. A. van Vugt, Project MinE ALS Sequencing Consortium, Scott P. Allen, Nicolas Locker, Ianthe Pitout, Susan Fletcher, Patrick R. Onck, Olivier Duss, Johnathan Cooper-Knock, Tatyana A. Shelkovnikova","doi":"10.1038/s41556-026-01895-y","DOIUrl":"10.1038/s41556-026-01895-y","url":null,"abstract":"The paraspeckle is a disease-relevant biomolecular condensate assembled from long non-coding RNA (lncRNA) NEAT1_2 ribonucleoprotein particles. Paraspeckle biogenesis is suppressed in normal tissues, yet it can be rapidly upregulated under stress. Here we demonstrate that a neurodegeneration-linked RNA-binding protein TDP-43 inhibits NEAT1_2 ribonucleoprotein particle condensation into the paraspeckle, in a concentration-dependent manner, which requires its intact polymerization and RNA binding. This effect is counterbalanced by core paraspeckle proteins such as FUS. Below disruptive concentrations, TDP-43 can be recruited into paraspeckles, forming non-liquid clusters. Under stress, TDP-43 sequestration into de novo nuclear condensates alleviates paraspeckle suppression and increases their dynamism. NEAT1_2 middle-part and 3′-end UG repeats mediate paraspeckle regulation by TDP-43 cotranscriptionally and post assembly, respectively. The deletion of the 3′-end UG repeat increases paraspeckle stability and cytoprotection in stressed human neurons. Consistently, longer 3′-end UG repeats are linked to shorter survival in the neurodegenerative disease amyotrophic lateral sclerosis. Thus, TDP-43 is a critical regulator of paraspeckle condensates linked to cytoprotection. Hodgson, Huang, Lang et al. show that TDP-43 limits ribonucleoprotein particle condensation into paraspeckles in a concentration- and polymerization-dependent manner. They also link paraspeckle condensation to stress response and neuroprotection.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 4","pages":"754-770"},"PeriodicalIF":19.1,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-026-01895-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478962","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":"Kinase KEY1 controls pyrenoid condensate size throughout the cell cycle by disrupting phase separation interactions","authors":"Shan He, Linnea M. Lemma, Alejandro Martinez-Calvo, Guanhua He, Jessica H. Hennacy, Lianyong Wang, Sabrina L. Ergun, Ashwani K. Rai, Colton Wang, Luke Bunday, Angelo Kayser-Browne, Quan Wang, Clifford P. Brangwynne, Ned S. Wingreen, Martin C. Jonikas","doi":"10.1038/s41556-026-01908-w","DOIUrl":"10.1038/s41556-026-01908-w","url":null,"abstract":"Biomolecular condensates spatially organize cellular functions, but the regulation of their size, number, dissolution and re-condensation is poorly understood. The pyrenoid, an algal biomolecular condensate that mediates one-third of global CO2 fixation, typically exists as one large condensate per chloroplast, but during cell division it transiently dissolves and reconfigures into multiple smaller condensates. Here, we identify a kinase, KEY1, in the model alga Chlamydomonas reinhardtii that regulates pyrenoid condensate size and number dynamics throughout the cell cycle and is necessary for normal pyrenoid function and growth. Unlike the wild type, key1 mutant cells have multiple smaller condensates throughout the cell cycle that fail to dissolve during cell division. We show that KEY1 localizes to the condensates and promotes their dissolution by disrupting interactions between their core constituents, the CO2-fixing enzyme Rubisco and its linker protein EPYC1, through EPYC1 phosphorylation. We develop a biophysical model that recapitulates KEY1-mediated condensate size and number regulation and suggests a mechanism for controlling condensate position. These data provide a foundation for the mechanistic understanding of the regulation of size, number, position and dissolution in pyrenoids and other biomolecular condensates. He et al. identify a central regulator of condensate size and dynamics in the Chlamydomonas CO2-fixing condensate, the pyrenoid. KEY1 phosphorylates EPYC1, a linker protein for Rubisco, to maintain pyrenoid size and number through the cell cycle.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 4","pages":"725-738"},"PeriodicalIF":19.1,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-026-01908-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465342","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}