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.
十-十一易位(TET)二氧合酶家族在细胞分裂和品系分化过程中维持稳定的局部 DNA 去甲基化。作为 TET 酶的主要催化产物,5-羟甲基胞嘧啶以组织依赖的方式选择性地富集在特定的基因组区域,如增强子。然而,这种选择性的内在机制仍未解决。在这里,我们揭示了 TET2 中的一个低复杂性插入结构域,它能促进 TET2 与表观遗传调节剂(如 UTX 和 MLL4)的生物分子缩聚。这种共同凝结为 DNA 的精确去甲基化创造了有利的染色质环境。破坏低复杂性插入介导的缩聚会改变 TET2 的基因组结合,从而导致杂乱的 DNA 去甲基化和基因组重组。这些变化会影响与白血病发生有关的关键基因的表达,从而抑制白血病细胞的增殖。总之,这项研究证实了 TET2 冷凝在协调精确的 DNA 去甲基化和基因转录以支持肿瘤细胞生长方面的关键作用。
{"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":"https://doi.org/10.1038/s41556-024-01496-7","url":null,"abstract":"<p>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.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"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}
Pub Date : 2024-09-05DOI: 10.1038/s41556-024-01500-0
Christian de Caestecker, Ian G. Macara
Despite decades of research, apical sorting of epithelial membrane proteins remains incompletely understood. We noted that apical cytoplasmic domains are smaller than those of basolateral proteins; however, the reason for this discrepancy is unknown. Here we used a synthetic biology approach to investigate whether a size barrier at the Golgi apparatus might hinder apical sorting of proteins with large cytoplasmic tails. We focused on Crb3, Ace2 and Muc1 as representative apical proteins with short cytoplasmic tails. By incorporating a streptavidin-binding peptide, these proteins can be trapped in the endoplasmic reticulum until addition of biotin, which triggers synchronous release to the Golgi and subsequent transport to the apical cortex. Strikingly, increasing the size of their cytoplasmic domains caused partial mislocalization to the basolateral cortex and significantly delayed Golgi departure. Moreover, N-glycosylation of ‘large’ Crb3 was delayed, and ‘small’ Crb3 segregated into spatially distinct Golgi regions. Biologically, Crb3 forms a complex through its cytoplasmic tail with the Pals1 protein, which could also delay departure, but although associated at the endoplasmic reticulum and Golgi, Pals1 disassociated before Crb3 departure. Notably, a non-dissociable mutant Pals1 hampered the exit of Crb3. We conclude that, unexpectedly, a size filter at the Golgi facilitates apical sorting of proteins with small cytoplasmic domains and that timely release of Pals1, to reduce cytoplasmic domain size, is essential for normal Crb3 sorting.
{"title":"A size filter at the Golgi regulates apical membrane protein sorting","authors":"Christian de Caestecker, Ian G. Macara","doi":"10.1038/s41556-024-01500-0","DOIUrl":"https://doi.org/10.1038/s41556-024-01500-0","url":null,"abstract":"<p>Despite decades of research, apical sorting of epithelial membrane proteins remains incompletely understood. We noted that apical cytoplasmic domains are smaller than those of basolateral proteins; however, the reason for this discrepancy is unknown. Here we used a synthetic biology approach to investigate whether a size barrier at the Golgi apparatus might hinder apical sorting of proteins with large cytoplasmic tails. We focused on Crb3, Ace2 and Muc1 as representative apical proteins with short cytoplasmic tails. By incorporating a streptavidin-binding peptide, these proteins can be trapped in the endoplasmic reticulum until addition of biotin, which triggers synchronous release to the Golgi and subsequent transport to the apical cortex. Strikingly, increasing the size of their cytoplasmic domains caused partial mislocalization to the basolateral cortex and significantly delayed Golgi departure. Moreover, N-glycosylation of ‘large’ Crb3 was delayed, and ‘small’ Crb3 segregated into spatially distinct Golgi regions. Biologically, Crb3 forms a complex through its cytoplasmic tail with the Pals1 protein, which could also delay departure, but although associated at the endoplasmic reticulum and Golgi, Pals1 disassociated before Crb3 departure. Notably, a non-dissociable mutant Pals1 hampered the exit of Crb3. We conclude that, unexpectedly, a size filter at the Golgi facilitates apical sorting of proteins with small cytoplasmic domains and that timely release of Pals1, to reduce cytoplasmic domain size, is essential for normal Crb3 sorting.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138031","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}
Human pancreatic cancer is characterized by the molecular diversity encompassing native duct-like and squamous cell-like identities, but mechanisms underlying squamous transdifferentiation have remained elusive. To comprehensively capture the molecular diversity of human pancreatic cancer, we here profiled 65 patient-derived pancreatic cancer organoid lines, including six adenosquamous carcinoma lines. H3K27me3-mediated erasure of the ductal lineage specifiers and hijacking of the TP63-driven squamous-cell programme drove squamous-cell commitment, providing survival benefit in a Wnt-deficient environment and hypoxic conditions. Gene engineering of normal pancreatic duct organoids revealed that GATA6 loss and a Wnt-deficient environment, in concert with genetic or hypoxia-mediated inactivation of KDM6A, facilitate squamous reprogramming, which in turn enhances environmental fitness. EZH2 inhibition counterbalanced the epigenetic bias and curbed the growth of adenosquamous cancer organoids. Our results demonstrate how an adversarial microenvironment dictates the molecular and histological evolution of human pancreatic cancer and provide insights into the principles and significance of lineage conversion in human cancer.
{"title":"Wnt-deficient and hypoxic environment orchestrates squamous reprogramming of human pancreatic ductal adenocarcinoma","authors":"Hiroki Tamagawa, Masayuki Fujii, Kazuhiro Togasaki, Takashi Seino, Shintaro Kawasaki, Ai Takano, Kohta Toshimitsu, Sirirat Takahashi, Yuki Ohta, Mami Matano, Kenta Kawasaki, Yujiro Machida, Shigeki Sekine, Akihito Machinaga, Ken Sasai, Yuzo Kodama, Nobuyuki Kakiuchi, Seishi Ogawa, Tomonori Hirano, Hiroshi Seno, Minoru Kitago, Yuko Kitagawa, Eisuke Iwasaki, Takanori Kanai, Toshiro Sato","doi":"10.1038/s41556-024-01498-5","DOIUrl":"https://doi.org/10.1038/s41556-024-01498-5","url":null,"abstract":"<p>Human pancreatic cancer is characterized by the molecular diversity encompassing native duct-like and squamous cell-like identities, but mechanisms underlying squamous transdifferentiation have remained elusive. To comprehensively capture the molecular diversity of human pancreatic cancer, we here profiled 65 patient-derived pancreatic cancer organoid lines, including six adenosquamous carcinoma lines. H3K27me3-mediated erasure of the ductal lineage specifiers and hijacking of the TP63-driven squamous-cell programme drove squamous-cell commitment, providing survival benefit in a Wnt-deficient environment and hypoxic conditions. Gene engineering of normal pancreatic duct organoids revealed that GATA6 loss and a Wnt-deficient environment, in concert with genetic or hypoxia-mediated inactivation of KDM6A, facilitate squamous reprogramming, which in turn enhances environmental fitness. EZH2 inhibition counterbalanced the epigenetic bias and curbed the growth of adenosquamous cancer organoids. Our results demonstrate how an adversarial microenvironment dictates the molecular and histological evolution of human pancreatic cancer and provide insights into the principles and significance of lineage conversion in human cancer.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142130879","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 : 2024-09-02DOI: 10.1038/s41556-024-01490-z
Kathryn Hockemeyer, Theodore Sakellaropoulos, Xufeng Chen, Olha Ivashkiv, Maria Sirenko, Hua Zhou, Giovanni Gambi, Elena Battistello, Kleopatra Avrampou, Zhengxi Sun, Maria Guillamot, Luis Chiriboga, George Jour, Igor Dolgalev, Kate Corrigan, Kamala Bhatt, Iman Osman, Aristotelis Tsirigos, Nikos Kourtis, Iannis Aifantis
Diverse cellular insults converge on activation of the heat shock factor 1 (HSF1), which regulates the proteotoxic stress response to maintain protein homoeostasis. HSF1 regulates numerous gene programmes beyond the proteotoxic stress response in a cell-type- and context-specific manner to promote malignancy. However, the role(s) of HSF1 in immune populations of the tumour microenvironment remain elusive. Here, we leverage an in vivo model of HSF1 activation and single-cell transcriptomic tumour profiling to show that augmented HSF1 activity in natural killer (NK) cells impairs cytotoxicity, cytokine production and subsequent anti-tumour immunity. Mechanistically, HSF1 directly binds and regulates the expression of key mediators of NK cell effector function. This work demonstrates that HSF1 regulates the immune response under the stress conditions of the tumour microenvironment. These findings have important implications for enhancing the efficacy of adoptive NK cell therapies and for designing combinatorial strategies including modulators of NK cell-mediated tumour killing.
热休克因子 1(HSF1)可调控蛋白毒性应激反应,以维持蛋白质平衡。除蛋白毒性应激反应外,HSF1 还以细胞类型和特定环境的方式调控许多基因程序,从而促进恶性肿瘤的发生。然而,HSF1 在肿瘤微环境免疫群体中的作用仍然难以捉摸。在这里,我们利用 HSF1 激活的体内模型和单细胞肿瘤转录组图谱分析表明,自然杀伤(NK)细胞中 HSF1 活性的增强会损害细胞毒性、细胞因子的产生和随后的抗肿瘤免疫。从机理上讲,HSF1 直接结合并调节 NK 细胞效应功能关键介质的表达。这项研究表明,HSF1 在肿瘤微环境的应激条件下调节免疫反应。这些发现对提高采用性 NK 细胞疗法的疗效以及设计包括 NK 细胞介导的肿瘤杀伤调节剂在内的组合策略具有重要意义。
{"title":"The stress response regulator HSF1 modulates natural killer cell anti-tumour immunity","authors":"Kathryn Hockemeyer, Theodore Sakellaropoulos, Xufeng Chen, Olha Ivashkiv, Maria Sirenko, Hua Zhou, Giovanni Gambi, Elena Battistello, Kleopatra Avrampou, Zhengxi Sun, Maria Guillamot, Luis Chiriboga, George Jour, Igor Dolgalev, Kate Corrigan, Kamala Bhatt, Iman Osman, Aristotelis Tsirigos, Nikos Kourtis, Iannis Aifantis","doi":"10.1038/s41556-024-01490-z","DOIUrl":"https://doi.org/10.1038/s41556-024-01490-z","url":null,"abstract":"<p>Diverse cellular insults converge on activation of the heat shock factor 1 (HSF1), which regulates the proteotoxic stress response to maintain protein homoeostasis. HSF1 regulates numerous gene programmes beyond the proteotoxic stress response in a cell-type- and context-specific manner to promote malignancy. However, the role(s) of HSF1 in immune populations of the tumour microenvironment remain elusive. Here, we leverage an in vivo model of HSF1 activation and single-cell transcriptomic tumour profiling to show that augmented HSF1 activity in natural killer (NK) cells impairs cytotoxicity, cytokine production and subsequent anti-tumour immunity. Mechanistically, HSF1 directly binds and regulates the expression of key mediators of NK cell effector function. This work demonstrates that HSF1 regulates the immune response under the stress conditions of the tumour microenvironment. These findings have important implications for enhancing the efficacy of adoptive NK cell therapies and for designing combinatorial strategies including modulators of NK cell-mediated tumour killing.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118146","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 : 2024-09-02DOI: 10.1038/s41556-024-01492-x
Alfonso Martinez Arias, Nicolas Rivron, Naomi Moris, Patrick Tam, Cantas Alev, Jianping Fu, Anna-Katerina Hadjantonakis, Jacob H. Hanna, Gabriella Minchiotti, Olivier Pourquie, Guojun Sheng, Liliana Solnica Krezel, Jesse V. Veenvliet, Aryeh Warmflash
Pluripotent stem cells are being used to generate models of early embryogenesis that are promising for discovery and translational research. To be useful, these models require critical consideration of their level of efficiency and fidelity to natural embryos. Here we propose criteria with which to raise the standards of stem-cell-based embryo models of human embryogenesis.
{"title":"Criteria for the standardization of stem-cell-based embryo models","authors":"Alfonso Martinez Arias, Nicolas Rivron, Naomi Moris, Patrick Tam, Cantas Alev, Jianping Fu, Anna-Katerina Hadjantonakis, Jacob H. Hanna, Gabriella Minchiotti, Olivier Pourquie, Guojun Sheng, Liliana Solnica Krezel, Jesse V. Veenvliet, Aryeh Warmflash","doi":"10.1038/s41556-024-01492-x","DOIUrl":"https://doi.org/10.1038/s41556-024-01492-x","url":null,"abstract":"Pluripotent stem cells are being used to generate models of early embryogenesis that are promising for discovery and translational research. To be useful, these models require critical consideration of their level of efficiency and fidelity to natural embryos. Here we propose criteria with which to raise the standards of stem-cell-based embryo models of human embryogenesis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118134","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 : 2024-09-02DOI: 10.1038/s41556-024-01491-y
Si Ming Man, Thirumala-Devi Kanneganti
Innate immunity, cell death and inflammation underpin many aspects of health and disease. Upon sensing pathogens, pathogen-associated molecular patterns or damage-associated molecular patterns, the innate immune system activates lytic, inflammatory cell death, such as pyroptosis and PANoptosis. These genetically defined, regulated cell death pathways not only contribute to the host defence against infectious disease, but also promote pathological manifestations leading to cancer and inflammatory diseases. Our understanding of the underlying mechanisms has grown rapidly in recent years. However, how dying cells, cell corpses and their liberated cytokines, chemokines and inflammatory signalling molecules are further sensed by innate immune cells, and their contribution to further amplify inflammation, trigger antigen presentation and activate adaptive immunity, is less clear. Here, we discuss how pattern-recognition and PANoptosome sensors in innate immune cells recognize and respond to cell-death signatures. We also highlight molecular targets of the innate immune response for potential therapeutic development. Man and Kanneganti discuss how pattern-recognition sensors in innate immune cells recognize and respond to cell-death signatures, and highlight molecular targets for potential therapeutic development.
{"title":"Innate immune sensing of cell death in disease and therapeutics","authors":"Si Ming Man, Thirumala-Devi Kanneganti","doi":"10.1038/s41556-024-01491-y","DOIUrl":"10.1038/s41556-024-01491-y","url":null,"abstract":"Innate immunity, cell death and inflammation underpin many aspects of health and disease. Upon sensing pathogens, pathogen-associated molecular patterns or damage-associated molecular patterns, the innate immune system activates lytic, inflammatory cell death, such as pyroptosis and PANoptosis. These genetically defined, regulated cell death pathways not only contribute to the host defence against infectious disease, but also promote pathological manifestations leading to cancer and inflammatory diseases. Our understanding of the underlying mechanisms has grown rapidly in recent years. However, how dying cells, cell corpses and their liberated cytokines, chemokines and inflammatory signalling molecules are further sensed by innate immune cells, and their contribution to further amplify inflammation, trigger antigen presentation and activate adaptive immunity, is less clear. Here, we discuss how pattern-recognition and PANoptosome sensors in innate immune cells recognize and respond to cell-death signatures. We also highlight molecular targets of the innate immune response for potential therapeutic development. Man and Kanneganti discuss how pattern-recognition sensors in innate immune cells recognize and respond to cell-death signatures, and highlight molecular targets for potential therapeutic development.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118147","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 : 2024-09-02DOI: 10.1038/s41556-024-01469-w
Daniel Dimitrov, Philipp Sven Lars Schäfer, Elias Farr, Pablo Rodriguez-Mier, Sebastian Lobentanzer, Pau Badia-i-Mompel, Aurelien Dugourd, Jovan Tanevski, Ricardo Omar Ramirez Flores, Julio Saez-Rodriguez
The growing availability of single-cell and spatially resolved transcriptomics has led to the development of many approaches to infer cell–cell communication, each capturing only a partial view of the complex landscape of intercellular signalling. Here we present LIANA+, a scalable framework built around a rich knowledge base to decode coordinated inter- and intracellular signalling events from single- and multi-condition datasets in both single-cell and spatially resolved data. By extending and unifying established methodologies, LIANA+ provides a comprehensive set of synergistic components to study cell–cell communication via diverse molecular mediators, including those measured in multi-omics data. LIANA+ is accessible at https://github.com/saezlab/liana-py with extensive vignettes ( https://liana-py.readthedocs.io/ ) and provides an all-in-one solution to intercellular communication inference. Dimitrov et al. present LIANA+, a framework that unifies and extends approaches to study inter- and intracellular signalling from diverse mediators, captured from single-cell, spatially resolved and multi-omics data.
{"title":"LIANA+ provides an all-in-one framework for cell–cell communication inference","authors":"Daniel Dimitrov, Philipp Sven Lars Schäfer, Elias Farr, Pablo Rodriguez-Mier, Sebastian Lobentanzer, Pau Badia-i-Mompel, Aurelien Dugourd, Jovan Tanevski, Ricardo Omar Ramirez Flores, Julio Saez-Rodriguez","doi":"10.1038/s41556-024-01469-w","DOIUrl":"10.1038/s41556-024-01469-w","url":null,"abstract":"The growing availability of single-cell and spatially resolved transcriptomics has led to the development of many approaches to infer cell–cell communication, each capturing only a partial view of the complex landscape of intercellular signalling. Here we present LIANA+, a scalable framework built around a rich knowledge base to decode coordinated inter- and intracellular signalling events from single- and multi-condition datasets in both single-cell and spatially resolved data. By extending and unifying established methodologies, LIANA+ provides a comprehensive set of synergistic components to study cell–cell communication via diverse molecular mediators, including those measured in multi-omics data. LIANA+ is accessible at https://github.com/saezlab/liana-py with extensive vignettes ( https://liana-py.readthedocs.io/ ) and provides an all-in-one solution to intercellular communication inference. Dimitrov et al. present LIANA+, a framework that unifies and extends approaches to study inter- and intracellular signalling from diverse mediators, captured from single-cell, spatially resolved and multi-omics data.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01469-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142117984","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}
The tumour microenvironment propagates stress responses in resident cells. In tumour-infiltrating natural killer (NK) cells, the HSF1 transcription factor binds to mediators of effector function, negatively regulating NK cytotoxicity. These findings provide important mechanistic insights that may enhance NK cell cancer therapy.
{"title":"HSF1 renders NK cells too stressed to respond","authors":"Yael Gruper, Aviad Ben-Shmuel, Ruth Scherz-Shouval","doi":"10.1038/s41556-024-01472-1","DOIUrl":"https://doi.org/10.1038/s41556-024-01472-1","url":null,"abstract":"The tumour microenvironment propagates stress responses in resident cells. In tumour-infiltrating natural killer (NK) cells, the HSF1 transcription factor binds to mediators of effector function, negatively regulating NK cytotoxicity. These findings provide important mechanistic insights that may enhance NK cell cancer therapy.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118133","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 : 2024-09-02DOI: 10.1038/s41556-024-01494-9
Matthew Eroglu, Tanner Zocher, Jacob McAuley, Rachel Webster, Maggie Z. X. Xiao, Bin Yu, Calvin Mok, W. Brent Derry
All known heritable phenotypic information in animals is transmitted by direct inheritance of nucleic acids, their covalent modifications or histone modifications that modulate expression of associated genomic regions. Nonetheless, numerous familial traits and disorders cannot be attributed to known heritable molecular factors. Here we identify amyloid-like protein structures that are stably inherited in wild-type animals and influence traits. Their perturbation by genetic, environmental or pharmacological treatments leads to developmental phenotypes that can be epigenetically passed onto progeny. Injection of amyloids isolated from different phenotypic backgrounds into naive animals recapitulates the associated phenotype in offspring. Genetic and proteomic analyses reveal that the 26S proteasome and its conserved regulators maintain heritable amyloids across generations, which enables proper germ cell sex differentiation. We propose that inheritance of a proteinaceous epigenetic memory coordinates developmental timing and patterning with the environment to confer adaptive fitness.
{"title":"Noncanonical inheritance of phenotypic information by protein amyloids","authors":"Matthew Eroglu, Tanner Zocher, Jacob McAuley, Rachel Webster, Maggie Z. X. Xiao, Bin Yu, Calvin Mok, W. Brent Derry","doi":"10.1038/s41556-024-01494-9","DOIUrl":"https://doi.org/10.1038/s41556-024-01494-9","url":null,"abstract":"<p>All known heritable phenotypic information in animals is transmitted by direct inheritance of nucleic acids, their covalent modifications or histone modifications that modulate expression of associated genomic regions. Nonetheless, numerous familial traits and disorders cannot be attributed to known heritable molecular factors. Here we identify amyloid-like protein structures that are stably inherited in wild-type animals and influence traits. Their perturbation by genetic, environmental or pharmacological treatments leads to developmental phenotypes that can be epigenetically passed onto progeny. Injection of amyloids isolated from different phenotypic backgrounds into naive animals recapitulates the associated phenotype in offspring. Genetic and proteomic analyses reveal that the 26S proteasome and its conserved regulators maintain heritable amyloids across generations, which enables proper germ cell sex differentiation. We propose that inheritance of a proteinaceous epigenetic memory coordinates developmental timing and patterning with the environment to confer adaptive fitness.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118148","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 : 2024-08-29DOI: 10.1038/s41556-024-01495-8
Xiaofu Cao, Shiying Huang, Mateusz M. Wagner, Yuan-Ting Cho, Din-Chi Chiu, Krista M. Wartchow, Artur Lazarian, Laura Beth McIntire, Marcus B. Smolka, Jeremy M. Baskin
Tools for acute manipulation of protein localization enable elucidation of spatiotemporally defined functions, but their reliance on exogenous triggers can interfere with cell physiology. This limitation is particularly apparent for studying mitosis, whose highly choreographed events are sensitive to perturbations. Here we exploit the serendipitous discovery of a phosphorylation-controlled, cell cycle-dependent localization change of the adaptor protein PLEKHA5 to develop a system for mitosis-specific protein recruitment to the plasma membrane that requires no exogenous stimulus. Mitosis-enabled anchor-away/recruiter system comprises an engineered, 15 kDa module derived from PLEKHA5 capable of recruiting functional protein cargoes to the plasma membrane during mitosis, either through direct fusion or via GFP–GFP nanobody interaction. Applications of the mitosis-enabled anchor-away/recruiter system include both knock sideways to rapidly extract proteins from their native localizations during mitosis and conditional recruitment of lipid-metabolizing enzymes for mitosis-selective editing of plasma membrane lipid content, without the need for exogenous triggers or perturbative synchronization methods.
{"title":"A phosphorylation-controlled switch confers cell cycle-dependent protein relocalization","authors":"Xiaofu Cao, Shiying Huang, Mateusz M. Wagner, Yuan-Ting Cho, Din-Chi Chiu, Krista M. Wartchow, Artur Lazarian, Laura Beth McIntire, Marcus B. Smolka, Jeremy M. Baskin","doi":"10.1038/s41556-024-01495-8","DOIUrl":"https://doi.org/10.1038/s41556-024-01495-8","url":null,"abstract":"<p>Tools for acute manipulation of protein localization enable elucidation of spatiotemporally defined functions, but their reliance on exogenous triggers can interfere with cell physiology. This limitation is particularly apparent for studying mitosis, whose highly choreographed events are sensitive to perturbations. Here we exploit the serendipitous discovery of a phosphorylation-controlled, cell cycle-dependent localization change of the adaptor protein PLEKHA5 to develop a system for mitosis-specific protein recruitment to the plasma membrane that requires no exogenous stimulus. Mitosis-enabled anchor-away/recruiter system comprises an engineered, 15 kDa module derived from PLEKHA5 capable of recruiting functional protein cargoes to the plasma membrane during mitosis, either through direct fusion or via GFP–GFP nanobody interaction. Applications of the mitosis-enabled anchor-away/recruiter system include both knock sideways to rapidly extract proteins from their native localizations during mitosis and conditional recruitment of lipid-metabolizing enzymes for mitosis-selective editing of plasma membrane lipid content, without the need for exogenous triggers or perturbative synchronization methods.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":21.3,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090018","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}