Protein ubiquitination plays a critical role in protein quality control in response to cellular stress. The excessive accumulation of ubiquitinated conjugates can be detrimental to cells and is recognized as a hallmark of multiple neurodegenerative diseases. However, an in-depth understanding of how the excessive ubiquitin chains are removed to maintain ubiquitin homeostasis post stress remains largely unclear. Here we found that caspase-2 (CASP2) accumulates in a ubiquitin and proteasome-positive biomolecular condensate, which we named ubstressome, following stress and functions as a deubiquitinase to remove overloaded ubiquitin chains on proteins prone to misfolding. Mechanistically, CASP2 binds to the poly-ubiquitinated conjugates through its allosteric ubiquitin-interacting motif-like region and decreases overloaded ubiquitin chains in a protease-dependent manner to promote substrate degradation. CASP2 deficiency in mice results in excessive accumulation of poly-ubiquitinated TAR DNA-binding protein 43, leading to motor defects. Our findings uncover a stress-evoked deubiquitinating activity of CASP2 in the maintenance of cellular ubiquitin homeostasis, which differs from the well-known roles of caspase in apoptosis and inflammation. These data also reveal unrecognized protein quality control functions of condensates in the removal of stress-induced ubiquitin chains. Ge, Zhou, Fu et al. find caspase-2 accumulates in biomolecular condensates with ubiquitin and proteasomal components and functions as a deubiquitinase following stress. Caspase-2-deficient mice accumulate poly-ubiquitinated TDP-43 and show motor defects.
蛋白质泛素化在应对细胞压力的蛋白质质量控制中发挥着关键作用。泛素化共轭物的过度积累会对细胞造成危害，被认为是多种神经退行性疾病的标志。然而，深入了解应激后如何清除过量泛素链以维持泛素平衡在很大程度上仍不清楚。在这里，我们发现在应激后，caspase-2（CASP2）会在泛素和蛋白酶体阳性的生物分子凝聚物（我们将其命名为ubstressome）中聚集，并发挥去泛素酶的功能，清除易发生错误折叠的蛋白质上过量的泛素链。从机理上讲，CASP2通过其异位泛素相互作用基序样区域与多泛素化共轭物结合，并以蛋白酶依赖的方式减少过载的泛素链，从而促进底物降解。小鼠缺乏 CASP2 会导致多泛素化的 TAR DNA 结合蛋白 43 过度积累，从而导致运动缺陷。我们的发现揭示了 CASP2 在维持细胞泛素平衡中的应激诱发的去泛素活性，这与众所周知的 caspase 在细胞凋亡和炎症中的作用不同。这些数据还揭示了冷凝物在清除应激诱导的泛素链过程中尚未被认识到的蛋白质质量控制功能。
{"title":"Caspase-2 is a condensate-mediated deubiquitinase in protein quality control","authors":"Yingwei Ge, Lijie Zhou, Yesheng Fu, Lijuan He, Yi Chen, Dingchang Li, Yuping Xie, Jun Yang, Haitao Wu, Hongmiao Dai, Zhiqiang Peng, Yong Zhang, Shaoqiong Yi, Bo Wu, Xin Zhang, Yangjun Zhang, Wantao Ying, Chun-Ping Cui, Cui Hua Liu, Lingqiang Zhang","doi":"10.1038/s41556-024-01522-8","DOIUrl":"10.1038/s41556-024-01522-8","url":null,"abstract":"Protein ubiquitination plays a critical role in protein quality control in response to cellular stress. The excessive accumulation of ubiquitinated conjugates can be detrimental to cells and is recognized as a hallmark of multiple neurodegenerative diseases. However, an in-depth understanding of how the excessive ubiquitin chains are removed to maintain ubiquitin homeostasis post stress remains largely unclear. Here we found that caspase-2 (CASP2) accumulates in a ubiquitin and proteasome-positive biomolecular condensate, which we named ubstressome, following stress and functions as a deubiquitinase to remove overloaded ubiquitin chains on proteins prone to misfolding. Mechanistically, CASP2 binds to the poly-ubiquitinated conjugates through its allosteric ubiquitin-interacting motif-like region and decreases overloaded ubiquitin chains in a protease-dependent manner to promote substrate degradation. CASP2 deficiency in mice results in excessive accumulation of poly-ubiquitinated TAR DNA-binding protein 43, leading to motor defects. Our findings uncover a stress-evoked deubiquitinating activity of CASP2 in the maintenance of cellular ubiquitin homeostasis, which differs from the well-known roles of caspase in apoptosis and inflammation. These data also reveal unrecognized protein quality control functions of condensates in the removal of stress-induced ubiquitin chains. Ge, Zhou, Fu et al. find caspase-2 accumulates in biomolecular condensates with ubiquitin and proteasomal components and functions as a deubiquitinase following stress. Caspase-2-deficient mice accumulate poly-ubiquitinated TDP-43 and show motor defects.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 11","pages":"1943-1957"},"PeriodicalIF":17.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01522-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555791","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}
Pub Date : 2024-10-16DOI: 10.1038/s41556-024-01524-6
Christopher Thomas, Tabea Lilian Marx, Sarah Mae Penir, Melina Schuh
During ovulation, an egg is released from an ovarian follicle, ready for fertilization. Ovulation occurs inside the body, impeding direct studies of its progression. Therefore, the exact mechanisms that control ovulation have remained unclear. Here we devised live imaging methods to study the entire process of ovulation in isolated mouse ovarian follicles. We show that ovulation proceeds through three distinct phases, follicle expansion (I), contraction (II) and rupture (III), culminating in the release of the egg. Follicle expansion is driven by hyaluronic acid secretion and an osmotic gradient-directed fluid influx into the follicle. Then, smooth muscle cells in the outer follicle drive follicle contraction. Follicle rupture begins with stigma formation, followed by the exit of follicular fluid and cumulus cells and the rapid release of the egg. These results establish a mechanistic framework for ovulation, a process of fundamental importance for reproduction. Thomas, Marx et al. devise a live imaging approach to spatiotemporally dissect mouse ovulation ex vivo.
{"title":"Ex vivo imaging reveals the spatiotemporal control of ovulation","authors":"Christopher Thomas, Tabea Lilian Marx, Sarah Mae Penir, Melina Schuh","doi":"10.1038/s41556-024-01524-6","DOIUrl":"10.1038/s41556-024-01524-6","url":null,"abstract":"During ovulation, an egg is released from an ovarian follicle, ready for fertilization. Ovulation occurs inside the body, impeding direct studies of its progression. Therefore, the exact mechanisms that control ovulation have remained unclear. Here we devised live imaging methods to study the entire process of ovulation in isolated mouse ovarian follicles. We show that ovulation proceeds through three distinct phases, follicle expansion (I), contraction (II) and rupture (III), culminating in the release of the egg. Follicle expansion is driven by hyaluronic acid secretion and an osmotic gradient-directed fluid influx into the follicle. Then, smooth muscle cells in the outer follicle drive follicle contraction. Follicle rupture begins with stigma formation, followed by the exit of follicular fluid and cumulus cells and the rapid release of the egg. These results establish a mechanistic framework for ovulation, a process of fundamental importance for reproduction. Thomas, Marx et al. devise a live imaging approach to spatiotemporally dissect mouse ovulation ex vivo.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 11","pages":"1997-2008"},"PeriodicalIF":17.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01524-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440228","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}
Pub Date : 2024-10-16DOI: 10.1038/s41556-024-01538-0
Douglas R. Green
After being activated, T lymphocytes must consume fuel for energy and biomaterials to sustain rapid proliferation and differentiation. As a consequence, waste is generated that must be managed. A new study now explores how activated CD8+ effector T cells handle ammonia, and how this impacts the survival and function of these cells.
T 淋巴细胞被激活后，必须消耗燃料作为能量和生物材料，以维持快速增殖和分化。因此，产生的废物必须加以管理。现在，一项新研究探讨了活化的 CD8+ 效应 T 细胞如何处理氨，以及这对这些细胞的存活和功能有何影响。
{"title":"Waste management and cell death in T cells","authors":"Douglas R. Green","doi":"10.1038/s41556-024-01538-0","DOIUrl":"10.1038/s41556-024-01538-0","url":null,"abstract":"After being activated, T lymphocytes must consume fuel for energy and biomaterials to sustain rapid proliferation and differentiation. As a consequence, waste is generated that must be managed. A new study now explores how activated CD8+ effector T cells handle ammonia, and how this impacts the survival and function of these cells.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 11","pages":"1826-1827"},"PeriodicalIF":17.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440226","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 : 2024-10-16DOI: 10.1038/s41556-024-01528-2
Thomas Brand
Modelling definitive haematopoiesis in organoids has been challenging. A study now develops blood-generating heart-forming organoids that display heart muscle, vascular endothelium formation and definitive haematopoiesis. This organoid represents an in vitro model of human embryonic circulatory system development.
{"title":"Now it’s getting bloody in cardiac organoids","authors":"Thomas Brand","doi":"10.1038/s41556-024-01528-2","DOIUrl":"10.1038/s41556-024-01528-2","url":null,"abstract":"Modelling definitive haematopoiesis in organoids has been challenging. A study now develops blood-generating heart-forming organoids that display heart muscle, vascular endothelium formation and definitive haematopoiesis. This organoid represents an in vitro model of human embryonic circulatory system development.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 11","pages":"1830-1831"},"PeriodicalIF":17.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440227","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 : 2024-10-10DOI: 10.1038/s41556-024-01517-5
Alexandra Schauer, Jesse V. Veenvliet
Hidden by the womb, early human development remains cloaked in mystery. To unveil developmental processes in health and disease, pluripotent stem cells can be coaxed into structures recapitulating aspects of the embryo. A study now establishes an advanced stem-cell-based model of the human embryonic trunk.
{"title":"Retinoid-enhanced human gastruloids","authors":"Alexandra Schauer, Jesse V. Veenvliet","doi":"10.1038/s41556-024-01517-5","DOIUrl":"10.1038/s41556-024-01517-5","url":null,"abstract":"Hidden by the womb, early human development remains cloaked in mystery. To unveil developmental processes in health and disease, pluripotent stem cells can be coaxed into structures recapitulating aspects of the embryo. A study now establishes an advanced stem-cell-based model of the human embryonic trunk.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 10","pages":"1634-1636"},"PeriodicalIF":17.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142397745","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 : 2024-10-09DOI: 10.1038/s41556-024-01523-7
Stephanie A. Fernandes, Danai-Dimitra Angelidaki, Julian Nüchel, Jiyoung Pan, Peter Gollwitzer, Yoav Elkis, Filippo Artoni, Sabine Wilhelm, Marija Kovacevic-Sarmiento, Constantinos Demetriades
Amino acid (AA) availability is a robust determinant of cell growth through controlling mechanistic/mammalian target of rapamycin complex 1 (mTORC1) activity. According to the predominant model in the field, AA sufficiency drives the recruitment and activation of mTORC1 on the lysosomal surface by the heterodimeric Rag GTPases, from where it coordinates the majority of cellular processes. Importantly, however, the teleonomy of the proposed lysosomal regulation of mTORC1 and where mTORC1 acts on its effector proteins remain enigmatic. Here, by using multiple pharmacological and genetic means to perturb the lysosomal AA-sensing and protein recycling machineries, we describe the spatial separation of mTORC1 regulation and downstream functions in mammalian cells, with lysosomal and non-lysosomal mTORC1 phosphorylating distinct substrates in response to different AA sources. Moreover, we reveal that a fraction of mTOR localizes at lysosomes owing to basal lysosomal proteolysis that locally supplies new AAs, even in cells grown in the presence of extracellular nutrients, whereas cytoplasmic mTORC1 is regulated by exogenous AAs. Overall, our study substantially expands our knowledge about the topology of mTORC1 regulation by AAs and hints at the existence of distinct, Rag- and lysosome-independent mechanisms that control its activity at other subcellular locations. Given the importance of mTORC1 signalling and AA sensing for human ageing and disease, our findings will probably pave the way towards the identification of function-specific mTORC1 regulators and thus highlight more effective targets for drug discovery against conditions with dysregulated mTORC1 activity in the future. Fernandes, Angelidaki et al. provide evidence supporting the spatial separation of mTORC1 activation and signalling. Differentially localized mTORC1 complexes phosphorylate distinct substrates in response to different amino acid supplies.
{"title":"Spatial and functional separation of mTORC1 signalling in response to different amino acid sources","authors":"Stephanie A. Fernandes, Danai-Dimitra Angelidaki, Julian Nüchel, Jiyoung Pan, Peter Gollwitzer, Yoav Elkis, Filippo Artoni, Sabine Wilhelm, Marija Kovacevic-Sarmiento, Constantinos Demetriades","doi":"10.1038/s41556-024-01523-7","DOIUrl":"10.1038/s41556-024-01523-7","url":null,"abstract":"Amino acid (AA) availability is a robust determinant of cell growth through controlling mechanistic/mammalian target of rapamycin complex 1 (mTORC1) activity. According to the predominant model in the field, AA sufficiency drives the recruitment and activation of mTORC1 on the lysosomal surface by the heterodimeric Rag GTPases, from where it coordinates the majority of cellular processes. Importantly, however, the teleonomy of the proposed lysosomal regulation of mTORC1 and where mTORC1 acts on its effector proteins remain enigmatic. Here, by using multiple pharmacological and genetic means to perturb the lysosomal AA-sensing and protein recycling machineries, we describe the spatial separation of mTORC1 regulation and downstream functions in mammalian cells, with lysosomal and non-lysosomal mTORC1 phosphorylating distinct substrates in response to different AA sources. Moreover, we reveal that a fraction of mTOR localizes at lysosomes owing to basal lysosomal proteolysis that locally supplies new AAs, even in cells grown in the presence of extracellular nutrients, whereas cytoplasmic mTORC1 is regulated by exogenous AAs. Overall, our study substantially expands our knowledge about the topology of mTORC1 regulation by AAs and hints at the existence of distinct, Rag- and lysosome-independent mechanisms that control its activity at other subcellular locations. Given the importance of mTORC1 signalling and AA sensing for human ageing and disease, our findings will probably pave the way towards the identification of function-specific mTORC1 regulators and thus highlight more effective targets for drug discovery against conditions with dysregulated mTORC1 activity in the future. Fernandes, Angelidaki et al. provide evidence supporting the spatial separation of mTORC1 activation and signalling. Differentially localized mTORC1 complexes phosphorylate distinct substrates in response to different amino acid supplies.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 11","pages":"1918-1933"},"PeriodicalIF":17.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01523-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385116","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}
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