Pub Date : 2024-07-30DOI: 10.1038/s41556-024-01473-0
Guoqing Lv, Qian Wang, Lin Lin, Qiao Ye, Xi Li, Qian Zhou, Xiangzhen Kong, Hongxia Deng, Fuping You, Hebing Chen, Song Wu, Lin Yuan
Cyclic GMP–AMP synthase (cGAS), a cytosolic DNA sensor that initiates a STING-dependent innate immune response, binds tightly to chromatin, where its catalytic activity is inhibited; however, mechanisms underlying cGAS recruitment to chromatin and functions of chromatin-bound cGAS (ccGAS) remain unclear. Here we show that mTORC2-mediated phosphorylation of human cGAS serine 37 promotes its chromatin localization in colorectal cancer cells, regulating cell growth and drug resistance independently of STING. We discovered that ccGAS recruits the SWI/SNF complex at specific chromatin regions, modifying expression of genes linked to glutaminolysis and DNA replication. Although ccGAS depletion inhibited cell growth, it induced chemoresistance to fluorouracil treatment in vitro and in vivo. Moreover, blocking kidney-type glutaminase, a downstream ccGAS target, overcame chemoresistance caused by ccGAS loss. Thus, ccGAS coordinates colorectal cancer plasticity and acquired chemoresistance through epigenetic patterning. Targeting both mTORC2–ccGAS and glutaminase provides a promising strategy to eliminate quiescent resistant cancer cells. Lv, Wang, Lin, Ye et al. report that mTORC2 phosphorylates cGAS to promote its chromatin localization and SWI/SNF recruitment to regulate target gene expression, thereby mediating plasticity and chemoresistance in colorectal cancer.
{"title":"mTORC2-driven chromatin cGAS mediates chemoresistance through epigenetic reprogramming in colorectal cancer","authors":"Guoqing Lv, Qian Wang, Lin Lin, Qiao Ye, Xi Li, Qian Zhou, Xiangzhen Kong, Hongxia Deng, Fuping You, Hebing Chen, Song Wu, Lin Yuan","doi":"10.1038/s41556-024-01473-0","DOIUrl":"10.1038/s41556-024-01473-0","url":null,"abstract":"Cyclic GMP–AMP synthase (cGAS), a cytosolic DNA sensor that initiates a STING-dependent innate immune response, binds tightly to chromatin, where its catalytic activity is inhibited; however, mechanisms underlying cGAS recruitment to chromatin and functions of chromatin-bound cGAS (ccGAS) remain unclear. Here we show that mTORC2-mediated phosphorylation of human cGAS serine 37 promotes its chromatin localization in colorectal cancer cells, regulating cell growth and drug resistance independently of STING. We discovered that ccGAS recruits the SWI/SNF complex at specific chromatin regions, modifying expression of genes linked to glutaminolysis and DNA replication. Although ccGAS depletion inhibited cell growth, it induced chemoresistance to fluorouracil treatment in vitro and in vivo. Moreover, blocking kidney-type glutaminase, a downstream ccGAS target, overcame chemoresistance caused by ccGAS loss. Thus, ccGAS coordinates colorectal cancer plasticity and acquired chemoresistance through epigenetic patterning. Targeting both mTORC2–ccGAS and glutaminase provides a promising strategy to eliminate quiescent resistant cancer cells. Lv, Wang, Lin, Ye et al. report that mTORC2 phosphorylates cGAS to promote its chromatin localization and SWI/SNF recruitment to regulate target gene expression, thereby mediating plasticity and chemoresistance in colorectal cancer.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01473-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141794611","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 : 2024-07-22DOI: 10.1038/s41556-024-01462-3
Rong-Yi Shi, Neng Zhou, Li Xuan, Zhong-Hui Jiang, Jing Xia, Jian-Min Zhu, Kai-Ming Chen, Guo-Li Zhou, Guo-Pan Yu, Jun Zhang, Chuanxin Huang, Ai-Bin Liang, Kai-Wei Liang, Hao Zhang, Jian-Feng Chen, Dachuan Zhang, Yi Zhong, Qi-Fa Liu, Guo-Qiang Chen, Cai-Wen Duan
Immunotherapy elicits a systemic antitumour immune response in peripheral circulating T cells. However, the T cell trafficking circuit between organs and their contributions to antitumour immunity remain largely unknown. Here we show in multiple mouse leukaemia models that high infiltration of leukaemic cells in bone marrow (BM) stimulates the transition of CD8+CD44+CD62L+ central memory T cells into CD8+CD44–CD62L– T cells, designated as inter-organ migratory T cells (TIM cells). TIM cells move from the BM to the intestine by upregulating integrin β7 and downregulating C-X-C motif chemokine receptor 3 during leukaemogenesis. Upon immunogenic chemotherapy, these BM-derived TIM cells return from the intestine to the BM through integrin α4–vascular cell adhesion molecule 1 interaction. Blocking C-X-C motif chemokine receptor 3 function boosts the immune response against leukaemia by enhancing T cell trafficking. This phenomenon can also be observed in patients with leukaemia. In summary, we identify an unrecognized intestine–BM trafficking circuit of T cells that contributes to the antitumour effects of immunogenic chemotherapy. Shi, Zhou, Xuan, Jiang et al. identify a population of CD8+ T cells that migrate from bone marrow to the small intestine during leukaemogenesis and then traffic back to contribute to anti-leukaemia immune responses during chemotherapy treatment.
免疫疗法会在外周循环 T 细胞中引发全身性抗肿瘤免疫反应。然而，器官间的 T 细胞运输回路及其对抗肿瘤免疫的贡献在很大程度上仍不为人所知。在这里，我们在多种小鼠白血病模型中发现，骨髓（BM）中白血病细胞的大量浸润刺激 CD8+CD44+CD62L+ 中枢记忆 T 细胞转变为 CD8+CD44-CD62L- T 细胞，即器官间迁移 T 细胞（TIM 细胞）。在白血病发生过程中，TIM 细胞通过上调整合素 β7 和下调 C-X-C motif 趋化因子受体 3 从 BM 转移到肠道。在接受免疫性化疗时，这些来源于 BM 的 TIM 细胞会通过整合素 α4 与血管细胞粘附分子 1 的相互作用从肠道返回 BM。阻断 C-X-C motif 趋化因子受体 3 的功能可通过加强 T 细胞的迁移来增强对白血病的免疫反应。在白血病患者身上也能观察到这种现象。总之，我们发现了一种未被发现的 T 细胞肠-BM 转运回路，它有助于免疫化疗的抗肿瘤效果。
{"title":"Trafficking circuit of CD8+ T cells between the intestine and bone marrow governs antitumour immunity","authors":"Rong-Yi Shi, Neng Zhou, Li Xuan, Zhong-Hui Jiang, Jing Xia, Jian-Min Zhu, Kai-Ming Chen, Guo-Li Zhou, Guo-Pan Yu, Jun Zhang, Chuanxin Huang, Ai-Bin Liang, Kai-Wei Liang, Hao Zhang, Jian-Feng Chen, Dachuan Zhang, Yi Zhong, Qi-Fa Liu, Guo-Qiang Chen, Cai-Wen Duan","doi":"10.1038/s41556-024-01462-3","DOIUrl":"10.1038/s41556-024-01462-3","url":null,"abstract":"Immunotherapy elicits a systemic antitumour immune response in peripheral circulating T cells. However, the T cell trafficking circuit between organs and their contributions to antitumour immunity remain largely unknown. Here we show in multiple mouse leukaemia models that high infiltration of leukaemic cells in bone marrow (BM) stimulates the transition of CD8+CD44+CD62L+ central memory T cells into CD8+CD44–CD62L– T cells, designated as inter-organ migratory T cells (TIM cells). TIM cells move from the BM to the intestine by upregulating integrin β7 and downregulating C-X-C motif chemokine receptor 3 during leukaemogenesis. Upon immunogenic chemotherapy, these BM-derived TIM cells return from the intestine to the BM through integrin α4–vascular cell adhesion molecule 1 interaction. Blocking C-X-C motif chemokine receptor 3 function boosts the immune response against leukaemia by enhancing T cell trafficking. This phenomenon can also be observed in patients with leukaemia. In summary, we identify an unrecognized intestine–BM trafficking circuit of T cells that contributes to the antitumour effects of immunogenic chemotherapy. Shi, Zhou, Xuan, Jiang et al. identify a population of CD8+ T cells that migrate from bone marrow to the small intestine during leukaemogenesis and then traffic back to contribute to anti-leukaemia immune responses during chemotherapy treatment.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141736942","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 : 2024-07-19DOI: 10.1038/s41556-024-01466-z
Mutations in the gene encoding the E3 ubiquitin ligase TRIAD3A cause adult-onset neurodegenerative disorders. We reveal that the ubiquitin ligase activity of TRIAD3A promotes its liquid–liquid phase separation. TRIAD3A co-partitions with tau into droplets, where tau forms fibrillar aggregates. TRIAD3A mediates the degradation of these aggregates through its role as an autophagy adaptor.
编码 E3 泛素连接酶 TRIAD3A 的基因突变会导致成人发病型神经退行性疾病。我们发现，TRIAD3A 的泛素连接酶活性可促进其液-液相分离。TRIAD3A 与 tau 共同分离成液滴，tau 在液滴中形成纤维状聚集体。TRIAD3A通过其作为自噬适配体的作用介导这些聚集体的降解。
{"title":"An E3 ligase and autophagy adaptor regulates tau proteostasis through nested phase separation","authors":"","doi":"10.1038/s41556-024-01466-z","DOIUrl":"10.1038/s41556-024-01466-z","url":null,"abstract":"Mutations in the gene encoding the E3 ubiquitin ligase TRIAD3A cause adult-onset neurodegenerative disorders. We reveal that the ubiquitin ligase activity of TRIAD3A promotes its liquid–liquid phase separation. TRIAD3A co-partitions with tau into droplets, where tau forms fibrillar aggregates. TRIAD3A mediates the degradation of these aggregates through its role as an autophagy adaptor.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141725940","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 : 2024-07-18DOI: 10.1038/s41556-024-01460-5
Olivier Saulnier, Jamie Zagozewski, Lisa Liang, Liam D. Hendrikse, Paul Layug, Victor Gordon, Kimberly A. Aldinger, Parthiv Haldipur, Stephanie Borlase, Ludivine Coudière-Morrison, Ting Cai, Emma Martell, Naomi M. Gonzales, Gareth Palidwor, Christopher J. Porter, Stéphane Richard, Tanveer Sharif, Kathleen J. Millen, Brad W. Doble, Michael D. Taylor, Tamra E. Werbowetski-Ogilvie
OTX2 is a transcription factor and known driver in medulloblastoma (MB), where it is amplified in a subset of tumours and overexpressed in most cases of group 3 and group 4 MB. Here we demonstrate a noncanonical role for OTX2 in group 3 MB alternative splicing. OTX2 associates with the large assembly of splicing regulators complex through protein–protein interactions and regulates a stem cell splicing program. OTX2 can directly or indirectly bind RNA and this may be partially independent of its DNA regulatory functions. OTX2 controls a pro-tumorigenic splicing program that is mirrored in human cerebellar rhombic lip origins. Among the OTX2-regulated differentially spliced genes, PPHLN1 is expressed in the most primitive rhombic lip stem cells, and targeting PPHLN1 splicing reduces tumour growth and enhances survival in vivo. These findings identify OTX2-mediated alternative splicing as a major determinant of cell fate decisions that drive group 3 MB progression. Werbowetski-Ogilvie, Taylor and colleagues report a noncanonical role for OTX2 in regulating alternative splicing and controlling a stem cell and pro-tumorigenic splicing program in group 3 medulloblastoma.
{"title":"A group 3 medulloblastoma stem cell program is maintained by OTX2-mediated alternative splicing","authors":"Olivier Saulnier, Jamie Zagozewski, Lisa Liang, Liam D. Hendrikse, Paul Layug, Victor Gordon, Kimberly A. Aldinger, Parthiv Haldipur, Stephanie Borlase, Ludivine Coudière-Morrison, Ting Cai, Emma Martell, Naomi M. Gonzales, Gareth Palidwor, Christopher J. Porter, Stéphane Richard, Tanveer Sharif, Kathleen J. Millen, Brad W. Doble, Michael D. Taylor, Tamra E. Werbowetski-Ogilvie","doi":"10.1038/s41556-024-01460-5","DOIUrl":"10.1038/s41556-024-01460-5","url":null,"abstract":"OTX2 is a transcription factor and known driver in medulloblastoma (MB), where it is amplified in a subset of tumours and overexpressed in most cases of group 3 and group 4 MB. Here we demonstrate a noncanonical role for OTX2 in group 3 MB alternative splicing. OTX2 associates with the large assembly of splicing regulators complex through protein–protein interactions and regulates a stem cell splicing program. OTX2 can directly or indirectly bind RNA and this may be partially independent of its DNA regulatory functions. OTX2 controls a pro-tumorigenic splicing program that is mirrored in human cerebellar rhombic lip origins. Among the OTX2-regulated differentially spliced genes, PPHLN1 is expressed in the most primitive rhombic lip stem cells, and targeting PPHLN1 splicing reduces tumour growth and enhances survival in vivo. These findings identify OTX2-mediated alternative splicing as a major determinant of cell fate decisions that drive group 3 MB progression. Werbowetski-Ogilvie, Taylor and colleagues report a noncanonical role for OTX2 in regulating alternative splicing and controlling a stem cell and pro-tumorigenic splicing program in group 3 medulloblastoma.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01460-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724014","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 : 2024-07-15DOI: 10.1038/s41556-024-01464-1
Annemarie Schwab, Zhigang Rao, Jie Zhang, André Gollowitzer, Katharina Siebenkäs, Nino Bindel, Elisabetta D’Avanzo, Ruthger van Roey, Yussuf Hajjaj, Ece Özel, Isabell Armstark, Leonhard Bereuter, Fengting Su, Julia Grander, Ehsan Bonyadi Rad, Arwin Groenewoud, Felix B. Engel, George W. Bell, Whitney S. Henry, José Pedro Friedmann Angeli, Marc P. Stemmler, Simone Brabletz, Andreas Koeberle, Thomas Brabletz
Therapy resistance and metastasis, the most fatal steps in cancer, are often triggered by a (partial) activation of the epithelial–mesenchymal transition (EMT) programme. A mesenchymal phenotype predisposes to ferroptosis, a cell death pathway exerted by an iron and oxygen-radical-mediated peroxidation of phospholipids containing polyunsaturated fatty acids. We here show that various forms of EMT activation, including TGFβ stimulation and acquired therapy resistance, increase ferroptosis susceptibility in cancer cells, which depends on the EMT transcription factor Zeb1. We demonstrate that Zeb1 increases the ratio of phospholipids containing pro-ferroptotic polyunsaturated fatty acids over cyto-protective monounsaturated fatty acids by modulating the differential expression of the underlying crucial enzymes stearoyl-Co-A desaturase 1 (SCD), fatty acid synthase (FASN), fatty acid desaturase 2 (FADS2), elongation of very long-chain fatty acid 5 (ELOVL5) and long-chain acyl-CoA synthetase 4 (ACSL4). Pharmacological inhibition of selected lipogenic enzymes (SCD and FADS2) allows the manipulation of ferroptosis sensitivity preferentially in high-Zeb1-expressing cancer cells. Our data are of potential translational relevance and suggest a combination of ferroptosis activators and SCD inhibitors for the treatment of aggressive cancers expressing high Zeb1. Schwab, Rao et al. report that Zeb1 mediates enhanced ferroptosis sensitivity in cancer cells after EMT activation, associated with altered expression of selected lipogenic enzymes and an subsequent increase in the PUFA:MUFA ratio.
{"title":"Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition","authors":"Annemarie Schwab, Zhigang Rao, Jie Zhang, André Gollowitzer, Katharina Siebenkäs, Nino Bindel, Elisabetta D’Avanzo, Ruthger van Roey, Yussuf Hajjaj, Ece Özel, Isabell Armstark, Leonhard Bereuter, Fengting Su, Julia Grander, Ehsan Bonyadi Rad, Arwin Groenewoud, Felix B. Engel, George W. Bell, Whitney S. Henry, José Pedro Friedmann Angeli, Marc P. Stemmler, Simone Brabletz, Andreas Koeberle, Thomas Brabletz","doi":"10.1038/s41556-024-01464-1","DOIUrl":"10.1038/s41556-024-01464-1","url":null,"abstract":"Therapy resistance and metastasis, the most fatal steps in cancer, are often triggered by a (partial) activation of the epithelial–mesenchymal transition (EMT) programme. A mesenchymal phenotype predisposes to ferroptosis, a cell death pathway exerted by an iron and oxygen-radical-mediated peroxidation of phospholipids containing polyunsaturated fatty acids. We here show that various forms of EMT activation, including TGFβ stimulation and acquired therapy resistance, increase ferroptosis susceptibility in cancer cells, which depends on the EMT transcription factor Zeb1. We demonstrate that Zeb1 increases the ratio of phospholipids containing pro-ferroptotic polyunsaturated fatty acids over cyto-protective monounsaturated fatty acids by modulating the differential expression of the underlying crucial enzymes stearoyl-Co-A desaturase 1 (SCD), fatty acid synthase (FASN), fatty acid desaturase 2 (FADS2), elongation of very long-chain fatty acid 5 (ELOVL5) and long-chain acyl-CoA synthetase 4 (ACSL4). Pharmacological inhibition of selected lipogenic enzymes (SCD and FADS2) allows the manipulation of ferroptosis sensitivity preferentially in high-Zeb1-expressing cancer cells. Our data are of potential translational relevance and suggest a combination of ferroptosis activators and SCD inhibitors for the treatment of aggressive cancers expressing high Zeb1. Schwab, Rao et al. report that Zeb1 mediates enhanced ferroptosis sensitivity in cancer cells after EMT activation, associated with altered expression of selected lipogenic enzymes and an subsequent increase in the PUFA:MUFA ratio.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01464-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618238","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 : 2024-07-15DOI: 10.1038/s41556-024-01461-4
Jiechao Zhou, Yang ‘an Chuang, Javier Redding-Ochoa, Rongzhen Zhang, Alexander J. Platero, Alexander H. Barrett, Juan C. Troncoso, Paul F. Worley, Wenchi Zhang
Multiple neurodegenerative diseases are characterized by aberrant proteinaceous accumulations of tau. Here, we report a RING-in-between-RING-type E3 ligase, TRIAD3A, that functions as an autophagy adaptor for tau. TRIAD3A(RNF216) is an essential gene with mutations causing age-progressive neurodegeneration. Our studies reveal that TRIAD3A E3 ligase catalyses mixed K11/K63 polyubiquitin chains and self-assembles into liquid–liquid phase separated (LLPS) droplets. Tau is ubiquitinated and accumulates within TRIAD3A LLPS droplets and, via LC3 interacting regions, targets tau for autophagic degradation. Unexpectedly, tau sequestered within TRIAD3A droplets rapidly converts to fibrillar aggregates without the transitional liquid phase of tau. In vivo studies show that TRIAD3A decreases the accumulation of phosphorylated tau in a tauopathy mouse model, and a disease-associated mutation of TRIAD3A increases accumulation of phosphorylated tau, exacerbates gliosis and increases pathological tau spreading. In human Alzheimer disease brain, TRIAD3A co-localizes with tau amyloid in multiple histological forms, suggesting a role in tau proteostasis. TRIAD3A is an autophagic adaptor that utilizes E3 ligase and LLPS as a mechanism to capture cargo and appears especially relevant to neurodegenerative diseases. Zhou et al. show that the E3 ubiquitin ligase TRIAD3A assembles into liquid–liquid phase-separated droplets that contain tau and promote conversion to fibrillar aggregates and tau autophagic degradation.
多种神经退行性疾病的特征是 tau 蛋白质的异常积累。在这里，我们报告了一种 RING-in-between-RING 型 E3 连接酶 TRIAD3A，它可作为 tau 的自噬适配体发挥作用。TRIAD3A(RNF216)是一个重要基因，其突变可导致年龄进行性神经退行性变。我们的研究发现，TRIAD3A E3连接酶能催化混合的K11/K63多泛素链，并自组装成液相-液相分离（LLPS）液滴。Tau被泛素化并聚集在TRIAD3A LLPS液滴中，并通过LC3相互作用区将tau作为自噬降解的靶标。意想不到的是，螯合在TRIAD3A液滴中的tau会迅速转化为纤维状聚集体，而不会出现tau的过渡液相。体内研究表明，TRIAD3A 可减少磷酸化 tau 在一种 tauopathy 小鼠模型中的积累，而与疾病相关的 TRIAD3A 基因突变会增加磷酸化 tau 的积累，加剧胶质病变并增加病理 tau 的扩散。在人类阿尔茨海默病大脑中，TRIAD3A以多种组织学形式与tau淀粉样蛋白共定位，表明其在tau蛋白稳态中发挥作用。TRIAD3A是一种自噬适配体，利用E3连接酶和LLPS作为捕获货物的机制，似乎与神经退行性疾病特别相关。
{"title":"The autophagy adaptor TRIAD3A promotes tau fibrillation by nested phase separation","authors":"Jiechao Zhou, Yang ‘an Chuang, Javier Redding-Ochoa, Rongzhen Zhang, Alexander J. Platero, Alexander H. Barrett, Juan C. Troncoso, Paul F. Worley, Wenchi Zhang","doi":"10.1038/s41556-024-01461-4","DOIUrl":"10.1038/s41556-024-01461-4","url":null,"abstract":"Multiple neurodegenerative diseases are characterized by aberrant proteinaceous accumulations of tau. Here, we report a RING-in-between-RING-type E3 ligase, TRIAD3A, that functions as an autophagy adaptor for tau. TRIAD3A(RNF216) is an essential gene with mutations causing age-progressive neurodegeneration. Our studies reveal that TRIAD3A E3 ligase catalyses mixed K11/K63 polyubiquitin chains and self-assembles into liquid–liquid phase separated (LLPS) droplets. Tau is ubiquitinated and accumulates within TRIAD3A LLPS droplets and, via LC3 interacting regions, targets tau for autophagic degradation. Unexpectedly, tau sequestered within TRIAD3A droplets rapidly converts to fibrillar aggregates without the transitional liquid phase of tau. In vivo studies show that TRIAD3A decreases the accumulation of phosphorylated tau in a tauopathy mouse model, and a disease-associated mutation of TRIAD3A increases accumulation of phosphorylated tau, exacerbates gliosis and increases pathological tau spreading. In human Alzheimer disease brain, TRIAD3A co-localizes with tau amyloid in multiple histological forms, suggesting a role in tau proteostasis. TRIAD3A is an autophagic adaptor that utilizes E3 ligase and LLPS as a mechanism to capture cargo and appears especially relevant to neurodegenerative diseases. Zhou et al. show that the E3 ubiquitin ligase TRIAD3A assembles into liquid–liquid phase-separated droplets that contain tau and promote conversion to fibrillar aggregates and tau autophagic degradation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618239","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 : 2024-07-12DOI: 10.1038/s41556-024-01459-y
Ruiqi Cai, Ori Scott, Gang Ye, Trieu Le, Ekambir Saran, Whijin Kwon, Subothan Inpanathan, Blayne A. Sayed, Roberto J. Botelho, Amra Saric, Stefan Uderhardt, Spencer A. Freeman
Polymers are endocytosed and hydrolysed by lysosomal enzymes to generate transportable solutes. While the transport of diverse organic solutes across the plasma membrane is well studied, their necessary ongoing efflux from the endocytic fluid into the cytosol is poorly appreciated by comparison. Myeloid cells that employ specialized types of endocytosis, that is, phagocytosis and macropinocytosis, are highly dependent on such transport pathways to prevent the build-up of hydrostatic pressure that otherwise offsets lysosomal dynamics including vesiculation, tubulation and fission. Without undergoing rupture, we found that lysosomes incurring this pressure owing to defects in solute efflux, are unable to retain luminal Na+, which collapses its gradient with the cytosol. This cation ‘leak’ is mediated by pressure-sensitive channels resident to lysosomes and leads to the inhibition of mTORC1, which is normally activated by Na+-coupled amino acid transporters driven by the Na+ gradient. As a consequence, the transcription factors TFEB/TFE3 are made active in macrophages with distended lysosomes. In addition to their role in lysosomal biogenesis, TFEB/TFE3 activation causes the release of MCP-1/CCL2. In catabolically stressed tissues, defects in efflux of solutes from the endocytic pathway leads to increased monocyte recruitment. Here we propose that macrophages respond to a pressure-sensing pathway on lysosomes to orchestrate lysosomal biogenesis as well as myeloid cell recruitment. Cai et al. show that, in lysosomes under hydrostatic pressure in macrophages, lysosomal mechanosensitive channels cause a cation leak. This leads to the inhibition of mTORC1, activation of TFEB/TFE3 and release of monocyte chemoattractant proteins.
{"title":"Pressure sensing of lysosomes enables control of TFEB responses in macrophages","authors":"Ruiqi Cai, Ori Scott, Gang Ye, Trieu Le, Ekambir Saran, Whijin Kwon, Subothan Inpanathan, Blayne A. Sayed, Roberto J. Botelho, Amra Saric, Stefan Uderhardt, Spencer A. Freeman","doi":"10.1038/s41556-024-01459-y","DOIUrl":"10.1038/s41556-024-01459-y","url":null,"abstract":"Polymers are endocytosed and hydrolysed by lysosomal enzymes to generate transportable solutes. While the transport of diverse organic solutes across the plasma membrane is well studied, their necessary ongoing efflux from the endocytic fluid into the cytosol is poorly appreciated by comparison. Myeloid cells that employ specialized types of endocytosis, that is, phagocytosis and macropinocytosis, are highly dependent on such transport pathways to prevent the build-up of hydrostatic pressure that otherwise offsets lysosomal dynamics including vesiculation, tubulation and fission. Without undergoing rupture, we found that lysosomes incurring this pressure owing to defects in solute efflux, are unable to retain luminal Na+, which collapses its gradient with the cytosol. This cation ‘leak’ is mediated by pressure-sensitive channels resident to lysosomes and leads to the inhibition of mTORC1, which is normally activated by Na+-coupled amino acid transporters driven by the Na+ gradient. As a consequence, the transcription factors TFEB/TFE3 are made active in macrophages with distended lysosomes. In addition to their role in lysosomal biogenesis, TFEB/TFE3 activation causes the release of MCP-1/CCL2. In catabolically stressed tissues, defects in efflux of solutes from the endocytic pathway leads to increased monocyte recruitment. Here we propose that macrophages respond to a pressure-sensing pathway on lysosomes to orchestrate lysosomal biogenesis as well as myeloid cell recruitment. Cai et al. show that, in lysosomes under hydrostatic pressure in macrophages, lysosomal mechanosensitive channels cause a cation leak. This leads to the inhibition of mTORC1, activation of TFEB/TFE3 and release of monocyte chemoattractant proteins.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597641","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}
Migrasomes are organelles that are generated by migrating cells. Here we report the key role of neutrophil-derived migrasomes in haemostasis. We found that a large number of neutrophil-derived migrasomes exist in the blood of mice and humans. Compared with neutrophil cell bodies and platelets, these migrasomes adsorb and enrich coagulation factors on the surface. Moreover, they are highly enriched with adhesion molecules, which enable them to preferentially accumulate at sites of injury, where they trigger platelet activation and clot formation. Depletion of neutrophils, or genetic reduction of the number of these migrasomes, significantly decreases platelet plug formation and impairs coagulation. These defects can be rescued by intravenous injection of purified neutrophil-derived migrasomes. Our study reveals neutrophil-derived migrasomes as a previously unrecognized essential component of the haemostasis system, which may shed light on the cause of various coagulation disorders and open therapeutic possibilities. Jiang et al. document an abundance of neutrophil-derived migrasomes in the blood of mice and humans and show that migrasomes are enriched in coagulation factors, accumulate at sites of injury and trigger platelet activation and clot formation.
{"title":"Neutrophil-derived migrasomes are an essential part of the coagulation system","authors":"Dong Jiang, Lin Jiao, Qing Li, Renxiang Xie, Haohao Jia, ShiHui Wang, Yining Chen, Siyuan Liu, Dandan Huang, Jiajia Zheng, Wenhao Song, Ying Li, JianFeng Chen, Jinsong Li, Binwu Ying, Li Yu","doi":"10.1038/s41556-024-01440-9","DOIUrl":"10.1038/s41556-024-01440-9","url":null,"abstract":"Migrasomes are organelles that are generated by migrating cells. Here we report the key role of neutrophil-derived migrasomes in haemostasis. We found that a large number of neutrophil-derived migrasomes exist in the blood of mice and humans. Compared with neutrophil cell bodies and platelets, these migrasomes adsorb and enrich coagulation factors on the surface. Moreover, they are highly enriched with adhesion molecules, which enable them to preferentially accumulate at sites of injury, where they trigger platelet activation and clot formation. Depletion of neutrophils, or genetic reduction of the number of these migrasomes, significantly decreases platelet plug formation and impairs coagulation. These defects can be rescued by intravenous injection of purified neutrophil-derived migrasomes. Our study reveals neutrophil-derived migrasomes as a previously unrecognized essential component of the haemostasis system, which may shed light on the cause of various coagulation disorders and open therapeutic possibilities. Jiang et al. document an abundance of neutrophil-derived migrasomes in the blood of mice and humans and show that migrasomes are enriched in coagulation factors, accumulate at sites of injury and trigger platelet activation and clot formation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01440-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597640","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 : 2024-07-12DOI: 10.1038/s41556-024-01463-2
Bo Zhou, Zhi-hong Jiang, Meng-ran Dai, Yuan-li Ai, Li Xiao, Chuan-qi Zhong, Liu-Zheng Wu, Qi-tao Chen, Hang-zi Chen, Qiao Wu
Gasdermin (GSDM) family proteins, known as the executors of pyroptosis, undergo protease-mediated cleavage before inducing pyroptosis. We here discovered a form of pyroptosis mediated by full-length (FL) GSDME without proteolytic cleavage. Intense ultraviolet-C irradiation-triggered DNA damage activates nuclear PARP1, leading to extensive formation of poly(ADP-ribose) (PAR) polymers. These PAR polymers are released to the cytoplasm, where they activate PARP5 to facilitate GSDME PARylation, resulting in a conformational change in GSDME that relieves autoinhibition. Moreover, ultraviolet-C irradiation promotes cytochrome c-catalysed cardiolipin peroxidation to elevate lipid reactive oxygen species, which is then sensed by PARylated GSDME, leading to oxidative oligomerization and plasma membrane targeting of FL-GSDME for perforation, eventually inducing pyroptosis. Reagents that concurrently stimulate PARylation and oxidation of FL-GSDME, synergistically promoting pyroptotic cell death. Overall, the present findings elucidate an unreported mechanism underlying the cleavage-independent function of GSDME in executing cell death, further enriching the paradigms and understanding of FL-GSDME-mediated pyroptosis. Zhou, Jiang, Dai et al report that upon ultraviolet-C radiation, full-length GSDME can induce pyroptosis without cleavage, likely due to conformational change and oxidative oligomerization after increased PARylation and mitochondrial lipid ROS levels.
{"title":"Full-length GSDME mediates pyroptosis independent from cleavage","authors":"Bo Zhou, Zhi-hong Jiang, Meng-ran Dai, Yuan-li Ai, Li Xiao, Chuan-qi Zhong, Liu-Zheng Wu, Qi-tao Chen, Hang-zi Chen, Qiao Wu","doi":"10.1038/s41556-024-01463-2","DOIUrl":"10.1038/s41556-024-01463-2","url":null,"abstract":"Gasdermin (GSDM) family proteins, known as the executors of pyroptosis, undergo protease-mediated cleavage before inducing pyroptosis. We here discovered a form of pyroptosis mediated by full-length (FL) GSDME without proteolytic cleavage. Intense ultraviolet-C irradiation-triggered DNA damage activates nuclear PARP1, leading to extensive formation of poly(ADP-ribose) (PAR) polymers. These PAR polymers are released to the cytoplasm, where they activate PARP5 to facilitate GSDME PARylation, resulting in a conformational change in GSDME that relieves autoinhibition. Moreover, ultraviolet-C irradiation promotes cytochrome c-catalysed cardiolipin peroxidation to elevate lipid reactive oxygen species, which is then sensed by PARylated GSDME, leading to oxidative oligomerization and plasma membrane targeting of FL-GSDME for perforation, eventually inducing pyroptosis. Reagents that concurrently stimulate PARylation and oxidation of FL-GSDME, synergistically promoting pyroptotic cell death. Overall, the present findings elucidate an unreported mechanism underlying the cleavage-independent function of GSDME in executing cell death, further enriching the paradigms and understanding of FL-GSDME-mediated pyroptosis. Zhou, Jiang, Dai et al report that upon ultraviolet-C radiation, full-length GSDME can induce pyroptosis without cleavage, likely due to conformational change and oxidative oligomerization after increased PARylation and mitochondrial lipid ROS levels.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597638","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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