Nature Cell Biology最新文献

{"title":"MLKL PARylation in the endothelial niche triggers angiocrine necroptosis to evade cancer immunosurveillance and chemotherapy","authors":"Nan Yang, Xiaoxue Li, Wenwen Huang, Gaili Ji, Wei Luo, Faming Jiang, Hao Zeng, Yali Chen, Yao Chen, Lina Qiao, Lu Chen, Shahin Rafii, Wei Wang, Ai Zheng, Bi-Sen Ding, Zhongwei Cao","doi":"10.1038/s41556-025-01740-8","DOIUrl":"10.1038/s41556-025-01740-8","url":null,"abstract":"Chemoresistance is the leading cause of cancer-related death. How chemotherapy subjugates the cellular crosstalk in the tumour microenvironment to cause chemoresistance remains to be defined. Here we find chemotherapy enables immunosuppressive SDF1+ endothelial niche to evade immunosurveillance in ovarian and breast cancers. We integrated human patient data and mouse models to show that chemotherapy selectively activates PARP1–SDF1 axis in tumour endothelial cells (ECs). This angiocrine SDF1 interferes with antitumour interplay between CXCL10+ macrophages and CXCR3+CD8+ T cells and promotes tumour progression in ovarian and breast cancers. Proteome-based screening revealed that endothelial PARP1 PARylates MLKL, a key necroptosis effector to upregulate angiocrine SDF1 in ECs. In sum, we identify PARylation-dependent necroptosis in tumour ECs as an important step in subverting the tumour microenvironment to evade immunosurveillance. Yang, Li, Huang, Ji, Luo, Jiang and colleagues report that chemotherapy induces MLKL PARylation and necroptosis in tumour endothelial cells, which in turn affects tumour-associated macrophages and CD8⁺ T cells, promoting immunosuppression and tumorigenesis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 9","pages":"1526-1542"},"PeriodicalIF":19.1,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995787","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":"Reaffirming the value of model organisms in training scientific minds","authors":"Miaoling Yang, Zhuo Du","doi":"10.1038/s41556-025-01754-2","DOIUrl":"10.1038/s41556-025-01754-2","url":null,"abstract":"As biomedical research prioritizes human models and translational promise, classic model organisms are increasingly dismissed. Here we argue that they have a lasting value, both in enabling discovery and in cultivating scientific thinking, by training researchers in systems reasoning, integrative thinking and independent inquiry.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1589-1591"},"PeriodicalIF":19.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987453","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":"NOX1 and NPY1R mark regional colon stem cell populations that serve as cancer origins in vivo","authors":"Maxime Gasnier, Tanysha Chi-Ying Chen, Swathi Yada, Sowmya Sagiraju, Yusuke Yoshikawa, Stefano Perna, Hui Yi Grace Lim, Bernett Lee, Nick Barker","doi":"10.1038/s41556-025-01763-1","DOIUrl":"10.1038/s41556-025-01763-1","url":null,"abstract":"Current colorectal cancer mouse models either lack colon specificity, limiting progression towards more advanced disease, or preclude evaluation of resident stem cells as cancer origins. Here we report the identification of NOX1 and NPY1R as cell-surface markers enriched in LGR5+ stem cells predominantly within the caecum and exclusively within the middle and distal colorectum, respectively. Selective dysregulation of Wnt signalling in NOX1+ or NPY1R+ stem cells using CreERT2 mouse lines drives colon cancer initiation, predominantly within the caecum and rectum respectively, establishing these stem cell populations as important sources of colon cancer. Selective conditional activation of Wnt signalling and oncogenic Kras in combination with loss of TRP53 in these stem cell compartments resulted in the development of advanced, invasive cancers. This study establishes CreERT2 drivers as valuable tools for studying stem cell contributions to colon cancer. Gasnier et al. identify NOX1 and NPY1R as markers of colon stem cells within the mouse caecum and the middle and distal colorectum, respectively. These stem cells contribute to the initiation of invasive colon tumours in mice.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 10","pages":"1632-1646"},"PeriodicalIF":19.1,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01763-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928010","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":"Genome-wide CRISPR screen identifies Menin and SUZ12 as regulators of human developmental timing","authors":"Nan Xu, Hyein S. Cho, James O. S. Hackland, Silvia Benito-Kwiecinski, Nathalie Saurat, Oliver Harschnitz, Marco Vincenzo Russo, Ralph Garippa, Gabriele Ciceri, Lorenz Studer","doi":"10.1038/s41556-025-01751-5","DOIUrl":"10.1038/s41556-025-01751-5","url":null,"abstract":"Embryonic development follows a conserved sequence of events across species, yet the pace of development is highly variable and particularly slow in humans. Species-specific developmental timing is largely recapitulated in stem cell models, suggesting a cell-intrinsic clock. Here we use directed differentiation of human embryonic stem cells into neuroectoderm to perform a whole-genome CRISPR-Cas9 knockout screen and show that the epigenetic factors Menin and SUZ12 modulate the speed of PAX6 expression during neural differentiation. Genetic and pharmacological loss-of-function of Menin or SUZ12 accelerate cell fate acquisition by shifting the balance of H3K4me3 and H3K27me3 at bivalent promoters, thereby priming key developmental genes for faster activation upon differentiation. We further reveal a synergistic interaction of Menin and SUZ12 in modulating differentiation speed. The acceleration effects were observed in definitive endoderm, cardiomyocyte and neuronal differentiation paradigms, pointing to chromatin bivalency as a general driver of timing across germ layers and developmental stages. Xu et al. perform a whole-genome CRISPR-Cas9 knockout screen using directed differentiation systems. They find that MEN1 and SUZ12 modulate human developmental timing by epigenetically controlling bivalent promoters of developmental genes.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 9","pages":"1411-1421"},"PeriodicalIF":19.1,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01751-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928012","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":"Synthetic ZFTA fusions pinpoint disordered protein domain acquisition as a mechanism of brain tumorigenesis","authors":"A. Arabzade, H. K. Shirnekhi, S. Varadharajan, S. M. Ippagunta, A. H. Phillips, N. Laboe, D. W. Baggett,  Wahiduzzaman, M. Jo, T. Zheng, R. Pathak, D. Gee, D. Bhimsaria, H. Wu, X. Gao, J. Liu, E. Emanus, A. Bland, A. Kardian, A. Hancock, B. Holcomb, T. Wright, T. Bugbee, H. Sun, M. Zhai, E. Caesar, M. Park, S. Tripathi, A. Shirinifard, K. Lowe, A. Khalighifar, R. A. Petersen, S. King, D. Stabley, A. Pitre, G. E. Campbell, C-G Park, W. T. Freyaldenhoven, B. Chandra, Y. Xia, E. Bonten, A. Achari, S. Kandikonda, A. Carisey, S. B. Pounds, J. Xu, D. W. Ellison, B. Deneen, K. C. Bertrand, R. W. Kriwacki, S. C. Mack","doi":"10.1038/s41556-025-01745-3","DOIUrl":"10.1038/s41556-025-01745-3","url":null,"abstract":"Over 95% of ependymomas that arise in the cortex are driven by a gene fusion involving the zinc finger translocation-associated (ZFTA) protein. Here, using super-resolution and lattice light-sheet microscopy, we demonstrate that the most frequent fusion variant, ZFTA–RELA (ZR), forms dynamic nuclear condensates that are required for oncogene expression and tumorigenesis. Mutagenesis studies of ZR reveal a key intrinsically disordered region (IDR) in RELA that governs condensate formation. Condensate-modulating IDR mutations introduced into ZR impaired its genomic occupancy at oncogenic loci and inhibited the recruitment of transcriptional effector proteins, such as MED1, BRD4 and RNA polymerase II. Using nuclear magnetic resonance spectroscopy, we examined the DNA-binding residues of the critical zinc finger (ZF1) found in ZR and characterized their significance for condensate formation, genomic binding and oncogene activation. We generated synthetic ZFTA fusion proteins where IDRs from known condensate-forming proteins were grafted into ZR. Synthetic ZFTA fusion oncoproteins utilizing IDRs from EWS and FUS restored condensate formation, oncogene transcription and tumour initiation in mice. These findings provide key insights into the oncogenic mechanism of ZR and the importance of IDR acquisition in fusion oncoproteins in brain cancer. Arabzade, Shirnekhi, Varadharajan, Ippagunta and colleagues show that the zinc finger translocation-associated (ZFTA) fusion oncoproteins gain intrinsically disordered regions, inducing nuclear condensate formation and oncogenic activation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 9","pages":"1496-1509"},"PeriodicalIF":19.1,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01745-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906074","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":"A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy","authors":"Mario Mauthe, Nicole van de Beek, Muriel Mari, Giel Korsten, Parisa Nobari, Kennith B. Castelino, Eduardo P. de Mattos, Ibtisam Ouhida, Jesse L. Dijkstra, Sabine Schipper-Krom, Laura R. de la Ballina, Monja R. Mueller, Anne Simonsen, Mark S. Hipp, Lukas C. Kapitein, Harm H. Kampinga, Fulvio Reggiori","doi":"10.1038/s41556-025-01747-1","DOIUrl":"10.1038/s41556-025-01747-1","url":null,"abstract":"Perturbations in protein quality control lead to the accumulation of misfolded proteins and protein aggregates, which can compromise health and lifespan. One key mechanism eliminating protein aggregates is aggrephagy, a selective type of autophagy. Here we reveal that fragmentation is required before autophagic clearance of various types of amorphous aggregates. This fragmentation requires both the 19S proteasomal regulatory particle and the DNAJB6-HSP70-HSP110 chaperone module. These two players are also essential for aggregate compaction that leads to the clustering of the selective autophagy receptors, which initiates the autophagic removal of the aggregates. We also found that the same players delay the formation of disease-associated huntingtin inclusions. This study assigns a novel function to the 19S regulatory particle and the DNAJB6-HSP70-HSP110 module, and uncovers that aggrephagy entails a piecemeal process, with relevance for proteinopathies. Mauthe et al. find that protein aggregate clearance requires fragmentation of the aggregate by a chaperone module and a proteasomal regulatory particle for recruitment and clustering of selective autophagy receptors to initiate phagophore formation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 9","pages":"1448-1464"},"PeriodicalIF":19.1,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01747-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906072","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":"Haematopoietic ageing in health and lifespan","authors":"Rebecca Andersson, Eva Mejia-Ramirez, Maria Carolina Florian","doi":"10.1038/s41556-025-01739-1","DOIUrl":"10.1038/s41556-025-01739-1","url":null,"abstract":"Ageing of the haematopoietic system is characterized by phenotypic and functional impairments that are driven by alterations of haematopoietic stem cells and of the bone marrow niche. Haematopoietic stem cells are responsible for the production of all the different cell types that constitute the blood, and their maintenance and differentiation must be tightly regulated during the whole life of an organism. Exciting new data emphasize that central aspects of blood ageing, ranging from inflammageing and immunosenescence to clonal haematopoiesis, are mechanistically linked to dysfunction and ageing of other tissues, supporting a central role for the haematopoietic system in this context. Here we review some of the recent findings with a focus on ageing of the haematopoietic system and provide an overview of its role in driving healthspan and lifespan of the whole organism. In this Review, Andersson et al. discuss emerging insights into ageing of the haematopoietic system and its role in driving organismal ageing, in particular inflammageing and immunosenescence, as well as in rejuvenation of the immune system.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 9","pages":"1398-1410"},"PeriodicalIF":19.1,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900356","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":"CHIP protects lysosomes from CLN4 mutant-induced membrane damage","authors":"Juhyung Lee, Natalie Chin, Jizhong Zou, Wan Nur Atiqah Binti Mazli, Michal Jarnik, Layla Saidi, Yue Xu, Eutteum Jeong, Jessica Suh, John Replogle, Michael E. Ward, Juan S. Bonifacino, Wei Zheng, Ling Hao, Yihong Ye","doi":"10.1038/s41556-025-01738-2","DOIUrl":"10.1038/s41556-025-01738-2","url":null,"abstract":"Understanding how cells mitigate lysosomal damage is critical for unravelling pathogenic mechanisms of lysosome-related diseases. Here we generate and characterize induced pluripotent stem cell (iPSC)-derived neurons (i3Neuron) bearing ceroid lipofuscinosis neuronal 4 (CLN4)-linked DNAJC5 mutations, which revealed extensive lysosomal abnormality in mutant neurons. In vitro membrane-damaging experiments establish lysosomal damages caused by lysosome-associated CLN4 mutant aggregates, as a critical pathogenic linchpin in CLN4-associated neurodegeneration. Intriguingly, in non-neuronal cells, a ubiquitin-dependent microautophagy mechanism downregulates CLN4 aggregates to counteract CLN4-associated lysotoxicity. Genome-wide CRISPR screens identify the ubiquitin ligase carboxyl terminus of Hsc70-interacting protein (CHIP) as a central microautophagy regulator that confers ubiquitin-dependent lysosome protection. Importantly, CHIP’s lysosome protection function is transferrable: ectopic CHIP improves lysosomal function in CLN4 i3Neurons and effectively alleviates lipofuscin accumulation and cell death in a Drosophila CLN4 disease model. Our study establishes CHIP-mediated microautophagy as a key organelle guardian that preserves lysosome integrity, offering new insights into therapeutic development for lysosome-related neurodegenerative diseases. Lee et al. use an aggregation-prone CLN4 mutant that causes lysosomal damage in neurons and show that in non-neurons, the ubiquitin ligase CHIP prevents CLN4-dependent lysotoxicity via microautophagy.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 9","pages":"1465-1481"},"PeriodicalIF":19.1,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900379","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 model for propagation of RNA structural memory through biomolecular condensates","authors":"Chen Cai, Jiancheng Yu, Xudong Zhang, Tong Zhou, Qi Chen","doi":"10.1038/s41556-025-01736-4","DOIUrl":"10.1038/s41556-025-01736-4","url":null,"abstract":"We hypothesize that stress-induced RNA structural changes, stabilized by RNA-binding proteins in biomolecular condensates, propagate via conformational catalysis in a prion-like manner across generations. Our model suggests that RNA structure encodes heritable memory, and its roles should be explored in epigenetic inheritance, evolutionary adaptation and disease.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 9","pages":"1381-1386"},"PeriodicalIF":19.1,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900504","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":"Discovery of a multi-chaperone condensate in the endoplasmic reticulum","authors":"","doi":"10.1038/s41556-025-01731-9","DOIUrl":"10.1038/s41556-025-01731-9","url":null,"abstract":"How multiple chaperones are organized to co-ordinate their activities has been unclear. We observed that the chaperone PDIA6 forms phase-separated condensates in the endoplasmic reticulum to which several additional chaperones are recruited. These multi-chaperone condensates constitute a dedicated endoplasmic reticulum sub-compartment that facilitates protein biogenesis and prevents protein misfolding and aggregation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 9","pages":"1394-1395"},"PeriodicalIF":19.1,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900573","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}