Pub Date : 2024-11-08DOI: 10.1038/s41556-024-01546-0
Kalki Kukreja, Bill Z. Jia, Sean E. McGeary, Nikit Patel, Sean G. Megason, Allon M. Klein
As tissues develop, cells divide and differentiate concurrently. Conflicting evidence shows that cell division is either dispensable or required for formation of cell types. Here, to determine the role of cell division in differentiation, we arrested the cell cycle in zebrafish embryos using two independent approaches and profiled them at single-cell resolution. We show that cell division is dispensable for differentiation of all embryonic tissues from early gastrulation to the end of segmentation. However, arresting cell division does slow down differentiation in some cell types, and it induces global stress responses. While differentiation is robust to blocking cell division, the proportions of cells across cell states are not, but show evidence of partial compensation. This work clarifies our understanding of the role of cell division in development and showcases the utility of combining embryo-wide perturbations with single-cell RNA sequencing to uncover the role of common biological processes across multiple tissues. Kukreja et al. show that blocking cell division in zebrafish does not affect differentiation of major cell types during gastrulation and segmentation, but it does decelerate differentiation of particular cell types and skews their proportions.
{"title":"Cell state transitions are decoupled from cell division during early embryo development","authors":"Kalki Kukreja, Bill Z. Jia, Sean E. McGeary, Nikit Patel, Sean G. Megason, Allon M. Klein","doi":"10.1038/s41556-024-01546-0","DOIUrl":"10.1038/s41556-024-01546-0","url":null,"abstract":"As tissues develop, cells divide and differentiate concurrently. Conflicting evidence shows that cell division is either dispensable or required for formation of cell types. Here, to determine the role of cell division in differentiation, we arrested the cell cycle in zebrafish embryos using two independent approaches and profiled them at single-cell resolution. We show that cell division is dispensable for differentiation of all embryonic tissues from early gastrulation to the end of segmentation. However, arresting cell division does slow down differentiation in some cell types, and it induces global stress responses. While differentiation is robust to blocking cell division, the proportions of cells across cell states are not, but show evidence of partial compensation. This work clarifies our understanding of the role of cell division in development and showcases the utility of combining embryo-wide perturbations with single-cell RNA sequencing to uncover the role of common biological processes across multiple tissues. Kukreja et al. show that blocking cell division in zebrafish does not affect differentiation of major cell types during gastrulation and segmentation, but it does decelerate differentiation of particular cell types and skews their proportions.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2035-2045"},"PeriodicalIF":17.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596427","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}
It has been established that N-acetyltransferase (murine NAT1 (mNAT1) and human NAT2 (hNAT2)) mediates insulin sensitivity in type 2 diabetes. Here we show that mNAT1 deficiency leads to a decrease in cellular spermidine—a natural polyamine exhibiting health-protective and anti-ageing effects—but understanding of its mechanism is limited. We identify that mNAT1 and hNAT2 modulate a type of post-translational modification involving acetylated spermidine, which we name acetylhypusination, on receptor-interacting serine/threonine-protein kinase 1 (RIPK1)—a key regulator of inflammation and cell death. Spermidine supplementation decreases RIPK1-mediated cell death and diabetic phenotypes induced by NAT1 deficiency in vivo. Furthermore, insulin resistance and diabetic kidney disease mediated by vascular pathology in NAT1-deficient mice can be blocked by inhibiting RIPK1. Finally, we demonstrate a decrease in spermidine and activation of RIPK1 in the vascular tissues of human patients with diabetes. Our study suggests a role for vascular pathology in diabetes onset and progression and identifies the inhibition of RIPK1 kinase as a potential therapeutic approach for the treatment of type 2 diabetes. Zhang et al. show that the activation of RIPK1 is suppressed by acetylhypusination in a spermidine-dependent manner. Disruption of this axis contributes to RIPK1-mediated vascular pathology to promote insulin resistance and diabetic kidney pathology.
{"title":"Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression","authors":"Tian Zhang, Weixin Fu, Haosong Zhang, Jianlong Li, Beizi Xing, Yuping Cai, Mengmeng Zhang, Xuheng Liu, Chunting Qi, Lihui Qian, Xinbo Hu, Hua Zhu, Shuailong Yang, Min Zhang, Jianping Liu, Ganquan Li, Yang Li, Rong Xiang, Zhengqiang Qi, Junhao Hu, Ying Li, Chengyu Zou, Qin Wang, Xia Jin, Rui Pang, Peiying Li, Junli Liu, Yaoyang Zhang, Zhaoyin Wang, Zheng-Jiang Zhu, Bing Shan, Junying Yuan","doi":"10.1038/s41556-024-01540-6","DOIUrl":"10.1038/s41556-024-01540-6","url":null,"abstract":"It has been established that N-acetyltransferase (murine NAT1 (mNAT1) and human NAT2 (hNAT2)) mediates insulin sensitivity in type 2 diabetes. Here we show that mNAT1 deficiency leads to a decrease in cellular spermidine—a natural polyamine exhibiting health-protective and anti-ageing effects—but understanding of its mechanism is limited. We identify that mNAT1 and hNAT2 modulate a type of post-translational modification involving acetylated spermidine, which we name acetylhypusination, on receptor-interacting serine/threonine-protein kinase 1 (RIPK1)—a key regulator of inflammation and cell death. Spermidine supplementation decreases RIPK1-mediated cell death and diabetic phenotypes induced by NAT1 deficiency in vivo. Furthermore, insulin resistance and diabetic kidney disease mediated by vascular pathology in NAT1-deficient mice can be blocked by inhibiting RIPK1. Finally, we demonstrate a decrease in spermidine and activation of RIPK1 in the vascular tissues of human patients with diabetes. Our study suggests a role for vascular pathology in diabetes onset and progression and identifies the inhibition of RIPK1 kinase as a potential therapeutic approach for the treatment of type 2 diabetes. Zhang et al. show that the activation of RIPK1 is suppressed by acetylhypusination in a spermidine-dependent manner. Disruption of this axis contributes to RIPK1-mediated vascular pathology to promote insulin resistance and diabetic kidney pathology.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2099-2114"},"PeriodicalIF":17.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594379","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 : 2024-11-07DOI: 10.1038/s41556-024-01542-4
We establish a mouse model of progressive diabetes induced by conditional NAT1 deficiency in vascular endothelial cells. NAT1 deficiency promotes the activation of RIPK1 owing to a type of post-translational modification mediated by spermidine and deoxyhyupisin synthase termed acetyl-hypusination. Our results suggest that inhibition of RIPK1 could be used to treat type 2 diabetes and vascular inflammation.
{"title":"Spermidine limits diabetes by modulating RIPK1-mediated cell death and inflammation","authors":"","doi":"10.1038/s41556-024-01542-4","DOIUrl":"10.1038/s41556-024-01542-4","url":null,"abstract":"We establish a mouse model of progressive diabetes induced by conditional NAT1 deficiency in vascular endothelial cells. NAT1 deficiency promotes the activation of RIPK1 owing to a type of post-translational modification mediated by spermidine and deoxyhyupisin synthase termed acetyl-hypusination. Our results suggest that inhibition of RIPK1 could be used to treat type 2 diabetes and vascular inflammation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2018-2019"},"PeriodicalIF":17.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594377","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}
RNA modification has emerged as an important epigenetic mechanism that controls abnormal metabolism and growth in acute myeloid leukaemia (AML). However, the roles of RNA N4-acetylcytidine (ac4C) modification in AML remain elusive. Here, we report that ac4C and its catalytic enzyme NAT10 drive leukaemogenesis and sustain self-renewal of leukaemic stem cells/leukaemia-initiating cells through reprogramming serine metabolism. Mechanistically, NAT10 facilitates exogenous serine uptake and de novo biosynthesis through ac4C-mediated translation enhancement of the serine transporter SLC1A4 and the transcription regulators HOXA9 and MENIN that activate transcription of serine synthesis pathway genes. We further characterize fludarabine as an inhibitor of NAT10 and demonstrate that pharmacological inhibition of NAT10 targets serine metabolic vulnerability, triggering substantial anti-leukaemia effects both in vitro and in vivo. Collectively, our study demonstrates the functional importance of ac4C and NAT10 in metabolism control and leukaemogenesis, providing insights into the potential of targeting NAT10 for AML therapy. Zhang, Huang, Wang, Long et al. report that NAT10 enhances serine uptake and biosynthesis in an ac4C-dependent mechanism, thereby promoting stemness and progression in acute myeloid leukaemia.
{"title":"NAT10-mediated mRNA N4-acetylcytidine reprograms serine metabolism to drive leukaemogenesis and stemness in acute myeloid leukaemia","authors":"Subo Zhang, Feng Huang, Yushuai Wang, Yifei Long, Yuanpei Li, Yalin Kang, Weiwei Gao, Xiuxin Zhang, Yueting Wen, Yun Wang, Lili Pan, Youmei Xia, Zhoutian Yang, Ying Yang, Hongjie Mo, Baiqing Li, Jiacheng Hu, Yunda Song, Shilin Zhang, Shenghua Dong, Xiao Du, Yingmin Li, Yadi Liu, Wenting Liao, Yijun Gao, Yaojun Zhang, Hongming Chen, Yang Liang, Jianjun Chen, Hengyou Weng, Huilin Huang","doi":"10.1038/s41556-024-01548-y","DOIUrl":"10.1038/s41556-024-01548-y","url":null,"abstract":"RNA modification has emerged as an important epigenetic mechanism that controls abnormal metabolism and growth in acute myeloid leukaemia (AML). However, the roles of RNA N4-acetylcytidine (ac4C) modification in AML remain elusive. Here, we report that ac4C and its catalytic enzyme NAT10 drive leukaemogenesis and sustain self-renewal of leukaemic stem cells/leukaemia-initiating cells through reprogramming serine metabolism. Mechanistically, NAT10 facilitates exogenous serine uptake and de novo biosynthesis through ac4C-mediated translation enhancement of the serine transporter SLC1A4 and the transcription regulators HOXA9 and MENIN that activate transcription of serine synthesis pathway genes. We further characterize fludarabine as an inhibitor of NAT10 and demonstrate that pharmacological inhibition of NAT10 targets serine metabolic vulnerability, triggering substantial anti-leukaemia effects both in vitro and in vivo. Collectively, our study demonstrates the functional importance of ac4C and NAT10 in metabolism control and leukaemogenesis, providing insights into the potential of targeting NAT10 for AML therapy. Zhang, Huang, Wang, Long et al. report that NAT10 enhances serine uptake and biosynthesis in an ac4C-dependent mechanism, thereby promoting stemness and progression in acute myeloid leukaemia.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2168-2182"},"PeriodicalIF":17.3,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01548-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588690","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 : 2024-11-01DOI: 10.1038/s41556-024-01541-5
Yue Lu, Tezin Walji, Benjamin Ravaux, Pratima Pandey, Changsong Yang, Bing Li, Delgermaa Luvsanjav, Kevin H. Lam, Ruihui Zhang, Zhou Luo, Chuanli Zhou, Christa W. Habela, Scott B. Snapper, Rong Li, David J. Goldhamer, David W. Schmidtke, Duojia Pan, Tatyana M. Svitkina, Elizabeth H. Chen
Invasive membrane protrusions play a central role in a variety of cellular processes. Unlike filopodia, invasive protrusions are mechanically stiff and propelled by branched actin polymerization. However, how branched actin filaments are organized to create finger-like invasive protrusions is unclear. Here, by examining the mammalian fusogenic synapse, where invasive protrusions are generated to promote cell membrane juxtaposition and fusion, we have uncovered the mechanism underlying invasive protrusion formation. We show that two nucleation-promoting factors for the Arp2/3 complex, WAVE and N-WASP, exhibit different localization patterns in the protrusions. Whereas WAVE is closely associated with the plasma membrane at the leading edge of the protrusive structures, N-WASP is enriched with WIP along the actin bundles in the shafts of the protrusions. During protrusion initiation and growth, the Arp2/3 complex nucleates branched actin filaments to generate low-density actin clouds in which the large GTPase dynamin organizes the new branched actin filaments into bundles, followed by actin-bundle stabilization by WIP, the latter functioning as an actin-bundling protein. Disruption of any of these components results in defective protrusions and failed myoblast fusion in cultured cells and mouse embryos. Together, our study has revealed the intricate spatiotemporal coordination between two nucleation-promoting factors and two actin-bundling proteins in building invasive protrusions at the mammalian fusogenic synapse and has general implications in understanding invasive protrusion formation in cellular processes beyond cell–cell fusion. Lu et al. reveal the spatiotemporal coordination between two nucleation-promoting factors, WAVE and N-WASP, and two actin-bundling proteins, dynamin and WIP, in generating invasive protrusions at the mammalian myoblast fusogenic synapse.
{"title":"Spatiotemporal coordination of actin regulators generates invasive protrusions in cell–cell fusion","authors":"Yue Lu, Tezin Walji, Benjamin Ravaux, Pratima Pandey, Changsong Yang, Bing Li, Delgermaa Luvsanjav, Kevin H. Lam, Ruihui Zhang, Zhou Luo, Chuanli Zhou, Christa W. Habela, Scott B. Snapper, Rong Li, David J. Goldhamer, David W. Schmidtke, Duojia Pan, Tatyana M. Svitkina, Elizabeth H. Chen","doi":"10.1038/s41556-024-01541-5","DOIUrl":"10.1038/s41556-024-01541-5","url":null,"abstract":"Invasive membrane protrusions play a central role in a variety of cellular processes. Unlike filopodia, invasive protrusions are mechanically stiff and propelled by branched actin polymerization. However, how branched actin filaments are organized to create finger-like invasive protrusions is unclear. Here, by examining the mammalian fusogenic synapse, where invasive protrusions are generated to promote cell membrane juxtaposition and fusion, we have uncovered the mechanism underlying invasive protrusion formation. We show that two nucleation-promoting factors for the Arp2/3 complex, WAVE and N-WASP, exhibit different localization patterns in the protrusions. Whereas WAVE is closely associated with the plasma membrane at the leading edge of the protrusive structures, N-WASP is enriched with WIP along the actin bundles in the shafts of the protrusions. During protrusion initiation and growth, the Arp2/3 complex nucleates branched actin filaments to generate low-density actin clouds in which the large GTPase dynamin organizes the new branched actin filaments into bundles, followed by actin-bundle stabilization by WIP, the latter functioning as an actin-bundling protein. Disruption of any of these components results in defective protrusions and failed myoblast fusion in cultured cells and mouse embryos. Together, our study has revealed the intricate spatiotemporal coordination between two nucleation-promoting factors and two actin-bundling proteins in building invasive protrusions at the mammalian fusogenic synapse and has general implications in understanding invasive protrusion formation in cellular processes beyond cell–cell fusion. Lu et al. reveal the spatiotemporal coordination between two nucleation-promoting factors, WAVE and N-WASP, and two actin-bundling proteins, dynamin and WIP, in generating invasive protrusions at the mammalian myoblast fusogenic synapse.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 11","pages":"1860-1877"},"PeriodicalIF":17.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142561876","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 : 2024-10-31DOI: 10.1038/s41556-024-01539-z
Tomas Knedlik, Marta Giacomello
Cell behaviour changes temporally in response to environmental and metabolic cues. This also applies to membrane contact sites (MCSs), where organelles come into close proximity to perform specific functions, such as lipid transfer or calcium signalling. Here, we discuss how MCSs change over time and whether MCSs exhibit circadian rhythmicity.
{"title":"Temporal dynamics of membrane contact sites","authors":"Tomas Knedlik, Marta Giacomello","doi":"10.1038/s41556-024-01539-z","DOIUrl":"10.1038/s41556-024-01539-z","url":null,"abstract":"Cell behaviour changes temporally in response to environmental and metabolic cues. This also applies to membrane contact sites (MCSs), where organelles come into close proximity to perform specific functions, such as lipid transfer or calcium signalling. Here, we discuss how MCSs change over time and whether MCSs exhibit circadian rhythmicity.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 11","pages":"1822-1824"},"PeriodicalIF":17.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555786","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}
DNA double-strand breaks (DSBs) must be repaired to ensure genome stability. Crucially, DSB-ends must be kept together for timely repair. In Saccharomyces cerevisiae, two pathways mediate DSB end-tethering. One employs the Mre11–Rad50–Xrs2 (MRX) complex to physically bridge DSB-ends. Another requires the conversion of DSB-ends into single-strand DNA (ssDNA) by Exo1, but the bridging proteins are unknown. We uncover that cohesin, its loader and Smc5/6 act with Exo1 to tether DSB-ends. Remarkably, cohesin specifically impaired in oligomerization fails to tether DSB-ends, revealing a function for cohesin oligomerization. In addition to the known importance of sister chromatid cohesion, microscopy-based microfluidic experiments unveil a role for cohesin in repair by ensuring DSB end-tethering. Altogether, our findings demonstrate that oligomerization of cohesin prevents DSB end-separation and promotes DSB repair, revealing a previously undescribed mode of action and role for cohesin in safeguarding genome integrity.
{"title":"Cohesin complex oligomerization maintains end-tethering at DNA double-strand breaks","authors":"Jamie Phipps, Mathias Toulouze, Cécile Ducrot, Rafaël Costa, Clémentine Brocas, Karine Dubrana","doi":"10.1038/s41556-024-01552-2","DOIUrl":"https://doi.org/10.1038/s41556-024-01552-2","url":null,"abstract":"<p>DNA double-strand breaks (DSBs) must be repaired to ensure genome stability. Crucially, DSB-ends must be kept together for timely repair. In <i>Saccharomyces cerevisiae</i>, two pathways mediate DSB end-tethering. One employs the Mre11–Rad50–Xrs2 (MRX) complex to physically bridge DSB-ends. Another requires the conversion of DSB-ends into single-strand DNA (ssDNA) by Exo1, but the bridging proteins are unknown. We uncover that cohesin, its loader and Smc5/6 act with Exo1 to tether DSB-ends. Remarkably, cohesin specifically impaired in oligomerization fails to tether DSB-ends, revealing a function for cohesin oligomerization. In addition to the known importance of sister chromatid cohesion, microscopy-based microfluidic experiments unveil a role for cohesin in repair by ensuring DSB end-tethering. Altogether, our findings demonstrate that oligomerization of cohesin prevents DSB end-separation and promotes DSB repair, revealing a previously undescribed mode of action and role for cohesin in safeguarding genome integrity.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"29 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555789","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}
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 : 2024-10-31DOI: 10.1038/s41556-024-01553-1
Masahiro Matsuwaka, Mami Kumon, Azusa Inoue
Facultative heterochromatin is formed by Polycomb repressive complex 2 (PRC2)-deposited H3K27 trimethylation (H3K27me3) and PRC1-deposited H2AK119 mono-ubiquitylation (H2AK119ub1). How it is newly established after fertilization remains unclear. To delineate the establishment kinetics, here we profiled the temporal dynamics of H3K27 dimethylation (H3K27me2), which represents the de novo PRC2 catalysis, in mouse preimplantation embryos. H3K27me2 is newly deposited at CpG islands (CGIs), the paternal X chromosome (Xp) and putative enhancers during the eight-cell-to-morula transition, all of which follow H2AK119ub1 deposition. We found that JARID2, a PRC2.2-specific accessory protein possessing an H2AK119ub1-binding ability, colocalizes with SUZ12 at CGIs and Xp in morula embryos. Upon JARID2 depletion, SUZ12 chromatin binding and H3K27me2 deposition were attenuated and H3K27 acetylation at putative enhancers was increased in morulae and subsequently H3K27me3 failed to be deposited in blastocysts. These data reveal that facultative heterochromatin is established by PRC2.2-driven stepwise H3K27 methylation along pre-deposited H2AK119ub1 during early embryogenesis.
{"title":"H3K27 dimethylation dynamics reveal stepwise establishment of facultative heterochromatin in early mouse embryos","authors":"Masahiro Matsuwaka, Mami Kumon, Azusa Inoue","doi":"10.1038/s41556-024-01553-1","DOIUrl":"https://doi.org/10.1038/s41556-024-01553-1","url":null,"abstract":"<p>Facultative heterochromatin is formed by Polycomb repressive complex 2 (PRC2)-deposited H3K27 trimethylation (H3K27me3) and PRC1-deposited H2AK119 mono-ubiquitylation (H2AK119ub1). How it is newly established after fertilization remains unclear. To delineate the establishment kinetics, here we profiled the temporal dynamics of H3K27 dimethylation (H3K27me2), which represents the de novo PRC2 catalysis, in mouse preimplantation embryos. H3K27me2 is newly deposited at CpG islands (CGIs), the paternal X chromosome (Xp) and putative enhancers during the eight-cell-to-morula transition, all of which follow H2AK119ub1 deposition. We found that JARID2, a PRC2.2-specific accessory protein possessing an H2AK119ub1-binding ability, colocalizes with SUZ12 at CGIs and Xp in morula embryos. Upon JARID2 depletion, SUZ12 chromatin binding and H3K27me2 deposition were attenuated and H3K27 acetylation at putative enhancers was increased in morulae and subsequently H3K27me3 failed to be deposited in blastocysts. These data reveal that facultative heterochromatin is established by PRC2.2-driven stepwise H3K27 methylation along pre-deposited H2AK119ub1 during early embryogenesis.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"42 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555790","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 : 2024-10-31DOI: 10.1038/s41556-024-01547-z
Jingchao Zhang, Greg Donahue, Michael B. Gilbert, Tomer Lapidot, Dario Nicetto, Kenneth S. Zaret
H3K9me3 heterochromatin, established by lysine methyltransferases (KMTs) and compacted by heterochromatin protein 1 (HP1) isoforms, represses alternative lineage genes and DNA repeats. Our understanding of H3K9me3 heterochromatin stability is presently limited to individual domains and DNA repeats. Here we engineered Suv39h2-knockout mouse embryonic stem cells to degrade remaining two H3K9me3 KMTs within 1 hour and found that both passive dilution and active removal contribute to H3K9me3 decay within 12–24 hours. We discovered four different H3K9me3 decay rates across the genome and chromatin features and transcription factor binding patterns that predict the stability classes. A ‘binary switch’ governs heterochromatin compaction, with HP1 rapidly dissociating from heterochromatin upon KMT depletion and a particular threshold level of HP1 limiting pioneer factor binding, chromatin opening and exit from pluripotency within 12 h. Unexpectedly, receding H3K9me3 domains unearth residual HP1β peaks enriched with heterochromatin-inducing proteins. Our findings reveal distinct H3K9me3 heterochromatin maintenance dynamics governing gene networks and repeats that together safeguard pluripotency. Zhang et al. uncover different dynamics underlying the maintenance and regulation of H3K9me3-enriched heterochromatin domains in mouse embryonic stem cells and propose that loss of H3K9me3 occurs through two distinct dynamic modes: passive dilution and active removal.
{"title":"Distinct H3K9me3 heterochromatin maintenance dynamics govern different gene programmes and repeats in pluripotent cells","authors":"Jingchao Zhang, Greg Donahue, Michael B. Gilbert, Tomer Lapidot, Dario Nicetto, Kenneth S. Zaret","doi":"10.1038/s41556-024-01547-z","DOIUrl":"10.1038/s41556-024-01547-z","url":null,"abstract":"H3K9me3 heterochromatin, established by lysine methyltransferases (KMTs) and compacted by heterochromatin protein 1 (HP1) isoforms, represses alternative lineage genes and DNA repeats. Our understanding of H3K9me3 heterochromatin stability is presently limited to individual domains and DNA repeats. Here we engineered Suv39h2-knockout mouse embryonic stem cells to degrade remaining two H3K9me3 KMTs within 1 hour and found that both passive dilution and active removal contribute to H3K9me3 decay within 12–24 hours. We discovered four different H3K9me3 decay rates across the genome and chromatin features and transcription factor binding patterns that predict the stability classes. A ‘binary switch’ governs heterochromatin compaction, with HP1 rapidly dissociating from heterochromatin upon KMT depletion and a particular threshold level of HP1 limiting pioneer factor binding, chromatin opening and exit from pluripotency within 12 h. Unexpectedly, receding H3K9me3 domains unearth residual HP1β peaks enriched with heterochromatin-inducing proteins. Our findings reveal distinct H3K9me3 heterochromatin maintenance dynamics governing gene networks and repeats that together safeguard pluripotency. Zhang et al. uncover different dynamics underlying the maintenance and regulation of H3K9me3-enriched heterochromatin domains in mouse embryonic stem cells and propose that loss of H3K9me3 occurs through two distinct dynamic modes: passive dilution and active removal.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2115-2128"},"PeriodicalIF":17.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555788","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}
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