{"title":"Navigating the biology of cell death","authors":"","doi":"10.1038/s41556-024-01515-7","DOIUrl":"10.1038/s41556-024-01515-7","url":null,"abstract":"This issue presents a Focus of specially commissioned articles that discuss cell death in its multiple forms, implications for homeostatic physiology and disease and outstanding questions in this expanding field.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 9","pages":"1373-1373"},"PeriodicalIF":17.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01515-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174386","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}
Xiaoxin Hao, Yichao Shen, Jun Liu, Angela Alexander, Ling Wu, Zhan Xu, Liqun Yu, Yang Gao, Fengshuo Liu, Hilda L. Chan, Che-Hsing Li, Yunfeng Ding, Weijie Zhang, David G. Edwards, Nan Chen, Azadeh Nasrazadani, Naoto T. Ueno, Bora Lim, Xiang H.-F. Zhang
{"title":"Solid tumour-induced systemic immunosuppression involves dichotomous myeloid–B cell interactions","authors":"Xiaoxin Hao, Yichao Shen, Jun Liu, Angela Alexander, Ling Wu, Zhan Xu, Liqun Yu, Yang Gao, Fengshuo Liu, Hilda L. Chan, Che-Hsing Li, Yunfeng Ding, Weijie Zhang, David G. Edwards, Nan Chen, Azadeh Nasrazadani, Naoto T. Ueno, Bora Lim, Xiang H.-F. Zhang","doi":"10.1038/s41556-024-01508-6","DOIUrl":"10.1038/s41556-024-01508-6","url":null,"abstract":"Solid tumours induce systemic immunosuppression that involves myeloid and T cells. B cell-related mechanisms remain relatively understudied. Here we discover two distinct patterns of tumour-induced B cell abnormality (TiBA; TiBA-1 and TiBA-2), both associated with abnormal myelopoiesis in the bone marrow. TiBA-1 probably results from the niche competition between pre-progenitor-B cells and myeloid progenitors, leading to a global reduction in downstream B cells. TiBA-2 is characterized by systemic accumulation of a unique early B cell population, driven by interaction with excessive neutrophils. Importantly, TiBA-2-associated early B cells foster the systemic accumulation of exhaustion-like T cells. Myeloid and B cells from the peripheral blood of patients with triple-negative breast cancer recapitulate the TiBA subtypes, and the distinct TiBA profile correlates with pathologic complete responses to standard-of-care immunotherapy. This study underscores the inter-patient diversity of tumour-induced systemic changes and emphasizes the need for treatments tailored to different B and myeloid cell abnormalities. Hao, Shen and colleagues identify and characterize two distinct types of myeloid–B cell interaction that may signal solid tumour-induced immunosuppression and can correlate with complete responses to immunotherapy in patients with breast cancer.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 11","pages":"1971-1983"},"PeriodicalIF":17.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170869","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":"Ferroptosis disseminates afar in development","authors":"Zhe Wang","doi":"10.1038/s41556-024-01504-w","DOIUrl":"10.1038/s41556-024-01504-w","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 9","pages":"1374-1374"},"PeriodicalIF":17.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174410","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}
Aleksander T. Szczurek, Emilia Dimitrova, Jessica R. Kelley, Neil P. Blackledge, Robert J. Klose
{"title":"The Polycomb system sustains promoters in a deep OFF state by limiting pre-initiation complex formation to counteract transcription","authors":"Aleksander T. Szczurek, Emilia Dimitrova, Jessica R. Kelley, Neil P. Blackledge, Robert J. Klose","doi":"10.1038/s41556-024-01493-w","DOIUrl":"10.1038/s41556-024-01493-w","url":null,"abstract":"The Polycomb system has fundamental roles in regulating gene expression during mammalian development. However, how it controls transcription to enable gene repression has remained enigmatic. Here, using rapid degron-based depletion coupled with live-cell transcription imaging and single-particle tracking, we show how the Polycomb system controls transcription in single cells. We discover that the Polycomb system is not a constitutive block to transcription but instead sustains a long-lived deep promoter OFF state, which limits the frequency with which the promoter can enter into a transcribing state. We demonstrate that Polycomb sustains this deep promoter OFF state by counteracting the binding of factors that enable early transcription pre-initiation complex formation and show that this is necessary for gene repression. Together, these important discoveries provide a rationale for how the Polycomb system controls transcription and suggests a universal mechanism that could enable the Polycomb system to constrain transcription across diverse cellular contexts. Combining degron-based depletion with live-cell transcription imaging and single-particle tracking, Szczurek et al. show that Polycomb keeps promoters in an OFF state by restricting the formation of the pre-initiation complex.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 10","pages":"1700-1711"},"PeriodicalIF":17.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01493-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170870","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":"Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells","authors":"Huafeng Zhang, Jincheng Liu, Wu Yuan, Qian Zhang, Xiao Luo, Yonggang Li, Yue’e Peng, Jingyu Feng, Xiaoyu Liu, Jie Chen, Yabo Zhou, Jiadi Lv, Nannan Zhou, Jingwei Ma, Ke Tang, Bo Huang","doi":"10.1038/s41556-024-01503-x","DOIUrl":"10.1038/s41556-024-01503-x","url":null,"abstract":"Ammonia is thought to be a cytotoxin and its increase in the blood impairs cell function. However, whether and how this toxin triggers cell death under pathophysiological conditions remains unclear. Here we show that ammonia induces a distinct form of cell death in effector T cells. We found that rapidly proliferating T cells use glutaminolysis to release ammonia in the mitochondria, which is then translocated to and stored in the lysosomes. Excessive ammonia accumulation increases lysosomal pH and results in the termination of lysosomal ammonia storage and ammonia reflux into mitochondria, leading to mitochondrial damage and cell death, which is characterized by lysosomal alkalization, mitochondrial swelling and impaired autophagic flux. Inhibition of glutaminolysis or blocking lysosomal alkalization prevents ammonia-induced T cell death and improves T cell-based antitumour immunotherapy. These findings identify a distinct form of cell death that differs from previously known mechanisms. Zhang, Liu and colleagues identify and characterize cell death in rapidly proliferating CD8+ T cells resulting from excessive ammonia accumulation and subsequent lysosomal dysfunction and mitochondrial damage.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 11","pages":"1892-1902"},"PeriodicalIF":17.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170871","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}
Markus F. Schliffka, Julien G. Dumortier, Diane Pelzer, Arghyadip Mukherjee, Jean-Léon Maître
{"title":"Inverse blebs operate as hydraulic pumps during mouse blastocyst formation","authors":"Markus F. Schliffka, Julien G. Dumortier, Diane Pelzer, Arghyadip Mukherjee, Jean-Léon Maître","doi":"10.1038/s41556-024-01501-z","DOIUrl":"10.1038/s41556-024-01501-z","url":null,"abstract":"During preimplantation development, mouse embryos form a fluid-filled lumen. Pressurized fluid fractures cell–cell contacts and accumulates into pockets, which coarsen into a single lumen. How the embryo controls intercellular fluid movement during coarsening is unknown. Here we report inverse blebs growing into cells at adhesive contacts. Throughout the embryo we observed hundreds of inverse blebs, each filling with intercellular fluid and retracting within a minute. Inverse blebs grow due to pressure build-up resulting from fluid accumulation and cell–cell adhesion, which locally confines fluid. Inverse blebs retract due to actomyosin contraction, practically pushing fluid within the intercellular space. Importantly, inverse blebs occur infrequently at contacts formed by multiple cells, which effectively serve as fluid sinks. Manipulation of the embryo topology reveals that without sinks inverse blebs pump fluid into one another in futile cycles. We propose that inverse blebs operate as hydraulic pumps to promote luminal coarsening, thereby constituting an instrument used by cells to control fluid movement. Schliffka et al. show that in the early mouse embryo, hemispherical intrusions, or inverse blebs, grow into cells at cell–cell adhesion sites in response to luminal fluid accumulation and pressure build-up, and may serve as pumps moving fluid into hydraulic sinks.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 10","pages":"1669-1677"},"PeriodicalIF":17.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170873","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":"Perturbing TET2 condensation promotes aberrant genome-wide DNA methylation and curtails leukaemia cell growth","authors":"Lei Guo, Tingting Hong, Yi-Tsang Lee, Xue Hu, Guokai Pan, Rongjie Zhao, Yuhan Yang, Jingwen Yang, Xiaoli Cai, Logan Rivera, Jie Liang, Rui Wang, Yaling Dou, Srikanth Kodali, Wenbo Li, Leng Han, Bruno Di Stefano, Yubin Zhou, Jia Li, Yun Huang","doi":"10.1038/s41556-024-01496-7","DOIUrl":"10.1038/s41556-024-01496-7","url":null,"abstract":"The ten-eleven translocation (TET) family of dioxygenases maintain stable local DNA demethylation during cell division and lineage specification. As the major catalytic product of TET enzymes, 5-hydroxymethylcytosine is selectively enriched at specific genomic regions, such as enhancers, in a tissue-dependent manner. However, the mechanisms underlying this selectivity remain unresolved. Here we unveil a low-complexity insert domain within TET2 that facilitates its biomolecular condensation with epigenetic modulators, such as UTX and MLL4. This co-condensation fosters a permissive chromatin environment for precise DNA demethylation. Disrupting low-complexity insert-mediated condensation alters the genomic binding of TET2 to cause promiscuous DNA demethylation and genome reorganization. These changes influence the expression of key genes implicated in leukaemogenesis to curtail leukaemia cell proliferation. Collectively, this study establishes the pivotal role of TET2 condensation in orchestrating precise DNA demethylation and gene transcription to support tumour cell growth. Guo, Hong et al. report that TET2 condensation maintains proper DNA demethylation at specific genomic loci, which can be targeted to alter gene expression and impair leukaemia growth.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2154-2167"},"PeriodicalIF":17.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158752","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}