Migrasomes, enriched with signaling molecules such as chemokines, cytokines and angiogenic factors, play a pivotal role in the spatially defined delivery of these molecules, influencing critical physiological processes including organ morphogenesis and angiogenesis. The mechanism governing the accumulation of signaling molecules in migrasomes has been elusive. In this study, we show that secretory proteins, including signaling proteins, are transported into migrasomes by secretory carriers via both the constitutive and regulated secretion pathways. During cell migration, a substantial portion of these carriers is redirected to the rear of the cell and actively transported into migrasomes, driven by the actin-dependent motor protein Myosin-5a. Once at the migrasomes, these carriers fuse with the migrasome membrane through SNARE-mediated mechanisms. Inhibiting migrasome formation significantly reduces secretion, suggesting migrasomes as a principal secretion route in migrating cells. Our findings reveal a specialized, highly localized secretion paradigm in migrating cells, conceptually paralleling the targeted neurotransmitter release observed in neuronal systems.
{"title":"Localized, highly efficient secretion of signaling proteins by migrasomes","authors":"Haifeng Jiao, Xiaopeng Li, Ying Li, Yuting Guo, Xiaoyu Hu, Takami Sho, Yiqun Luo, Jinyu Wang, Huizhen Cao, Wanqing Du, Dong Li, Li Yu","doi":"10.1038/s41422-024-00992-7","DOIUrl":"10.1038/s41422-024-00992-7","url":null,"abstract":"Migrasomes, enriched with signaling molecules such as chemokines, cytokines and angiogenic factors, play a pivotal role in the spatially defined delivery of these molecules, influencing critical physiological processes including organ morphogenesis and angiogenesis. The mechanism governing the accumulation of signaling molecules in migrasomes has been elusive. In this study, we show that secretory proteins, including signaling proteins, are transported into migrasomes by secretory carriers via both the constitutive and regulated secretion pathways. During cell migration, a substantial portion of these carriers is redirected to the rear of the cell and actively transported into migrasomes, driven by the actin-dependent motor protein Myosin-5a. Once at the migrasomes, these carriers fuse with the migrasome membrane through SNARE-mediated mechanisms. Inhibiting migrasome formation significantly reduces secretion, suggesting migrasomes as a principal secretion route in migrating cells. Our findings reveal a specialized, highly localized secretion paradigm in migrating cells, conceptually paralleling the targeted neurotransmitter release observed in neuronal systems.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-00992-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141448159","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 : 2024-06-24DOI: 10.1038/s41422-024-00994-5
Huanhuan Zhu, Weiqiang Lin, Aifu Lin
{"title":"ANT2: the first mammalian mitochondrial RNA transport translocon","authors":"Huanhuan Zhu, Weiqiang Lin, Aifu Lin","doi":"10.1038/s41422-024-00994-5","DOIUrl":"10.1038/s41422-024-00994-5","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-00994-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141444761","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 shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which we identify as a new substrate of AMPK activated in low glucose, is required for the low glucose-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527) and promotes the interaction of PDZD8 with and activation of glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis. In vivo, the AMPK-PDZD8-GLS1 axis is required for the enhancement of glutaminolysis as tested in the skeletal muscle tissues, which occurs earlier than the increase in fatty acid utilization during fasting. The enhanced glutaminolysis is also observed in macrophages in low glucose or under acute lipopolysaccharide (LPS) treatment. Consistent with a requirement of heightened glutaminolysis, the PDZD8-T527A mutation dampens the secretion of pro-inflammatory cytokines in macrophages in mice treated with LPS. Together, we have revealed an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis ahead of increased fatty acid utilization under glucose shortage.
{"title":"AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine","authors":"Mengqi Li, Yu Wang, Xiaoyan Wei, Wei-Feng Cai, Jianfeng Wu, Mingxia Zhu, Yongliang Wang, Yan-Hui Liu, Jinye Xiong, Qi Qu, Yan Chen, Xiao Tian, Luming Yao, Renxiang Xie, Xiaomin Li, Siwei Chen, Xi Huang, Cixiong Zhang, Changchuan Xie, Yaying Wu, Zheni Xu, Baoding Zhang, Bin Jiang, Zhi-Chao Wang, Qinxi Li, Gang Li, Shu-Yong Lin, Li Yu, Hai-Long Piao, Xianming Deng, Jiahuai Han, Chen-Song Zhang, Sheng-Cai Lin","doi":"10.1038/s41422-024-00985-6","DOIUrl":"10.1038/s41422-024-00985-6","url":null,"abstract":"The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which we identify as a new substrate of AMPK activated in low glucose, is required for the low glucose-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527) and promotes the interaction of PDZD8 with and activation of glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis. In vivo, the AMPK-PDZD8-GLS1 axis is required for the enhancement of glutaminolysis as tested in the skeletal muscle tissues, which occurs earlier than the increase in fatty acid utilization during fasting. The enhanced glutaminolysis is also observed in macrophages in low glucose or under acute lipopolysaccharide (LPS) treatment. Consistent with a requirement of heightened glutaminolysis, the PDZD8-T527A mutation dampens the secretion of pro-inflammatory cytokines in macrophages in mice treated with LPS. Together, we have revealed an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis ahead of increased fatty acid utilization under glucose shortage.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-00985-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426455","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 : 2024-06-10DOI: 10.1038/s41422-024-00987-4
Romane Thouenon, Grégory Verdeil
{"title":"Tumor microenvironment squeezes out the juice from T cells","authors":"Romane Thouenon, Grégory Verdeil","doi":"10.1038/s41422-024-00987-4","DOIUrl":"10.1038/s41422-024-00987-4","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-00987-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141298916","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}
Physiologically, the atria contract first, followed by the ventricles, which is the prerequisite for normal blood circulation. The above phenomenon of atrioventricular sequential contraction results from the characteristically slow conduction of electrical excitation of the atrioventricular node (AVN) between the atria and the ventricles. However, it is not clear what controls the conduction of electrical excitation within AVNs. Here, we find that AVN pacemaker cells (AVNPCs) possess an intact intrinsic GABAergic system, which plays a key role in electrical conduction from the atria to the ventricles. First, along with the discovery of abundant GABA-containing vesicles under the surface membranes of AVNPCs, key elements of the GABAergic system, including GABA metabolic enzymes, GABA receptors, and GABA transporters, were identified in AVNPCs. Second, GABA synchronously elicited GABA-gated currents in AVNPCs, which significantly weakened the excitability of AVNPCs. Third, the key molecular elements of the GABAergic system markedly modulated the conductivity of electrical excitation in the AVN. Fourth, GABAA receptor deficiency in AVNPCs accelerated atrioventricular conduction, which impaired the AVN’s protective potential against rapid ventricular frequency responses, increased susceptibility to lethal ventricular arrhythmias, and decreased the cardiac contractile function. Finally, interventions targeting the GABAergic system effectively prevented the occurrence and development of atrioventricular block. In summary, the endogenous GABAergic system in AVNPCs determines the slow conduction of electrical excitation within AVNs, thereby ensuring sequential atrioventricular contraction. The endogenous GABAergic system shows promise as a novel intervention target for cardiac arrhythmias.
{"title":"A GABAergic system in atrioventricular node pacemaker cells controls electrical conduction between the atria and ventricles","authors":"Dandan Liang, Liping Zhou, Huixing Zhou, Fulei Zhang, Guojian Fang, Junwei Leng, Yahan Wu, Yuemei Zhang, Anqi Yang, Yi Liu, Yi-Han Chen","doi":"10.1038/s41422-024-00980-x","DOIUrl":"10.1038/s41422-024-00980-x","url":null,"abstract":"Physiologically, the atria contract first, followed by the ventricles, which is the prerequisite for normal blood circulation. The above phenomenon of atrioventricular sequential contraction results from the characteristically slow conduction of electrical excitation of the atrioventricular node (AVN) between the atria and the ventricles. However, it is not clear what controls the conduction of electrical excitation within AVNs. Here, we find that AVN pacemaker cells (AVNPCs) possess an intact intrinsic GABAergic system, which plays a key role in electrical conduction from the atria to the ventricles. First, along with the discovery of abundant GABA-containing vesicles under the surface membranes of AVNPCs, key elements of the GABAergic system, including GABA metabolic enzymes, GABA receptors, and GABA transporters, were identified in AVNPCs. Second, GABA synchronously elicited GABA-gated currents in AVNPCs, which significantly weakened the excitability of AVNPCs. Third, the key molecular elements of the GABAergic system markedly modulated the conductivity of electrical excitation in the AVN. Fourth, GABAA receptor deficiency in AVNPCs accelerated atrioventricular conduction, which impaired the AVN’s protective potential against rapid ventricular frequency responses, increased susceptibility to lethal ventricular arrhythmias, and decreased the cardiac contractile function. Finally, interventions targeting the GABAergic system effectively prevented the occurrence and development of atrioventricular block. In summary, the endogenous GABAergic system in AVNPCs determines the slow conduction of electrical excitation within AVNs, thereby ensuring sequential atrioventricular contraction. The endogenous GABAergic system shows promise as a novel intervention target for cardiac arrhythmias.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-00980-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141287092","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 : 2024-06-04DOI: 10.1038/s41422-024-00981-w
Qiyin An, Yong Wang, Zhenhua Tian, Jie Han, Jinyue Li, Fumeng Liao, Feiyang Yu, Haiyan Zhao, Yancheng Wen, Heng Zhang, Zengqin Deng
Coupling distinct enzymatic effectors emerges as an efficient strategy for defense against phage infection in bacterial immune responses, such as the widely studied nuclease and cyclase activities in the type III CRISPR-Cas system. However, concerted enzymatic activities in other bacterial defense systems are poorly understood. Here, we biochemically and structurally characterize a two-component defense system DUF4297–HerA, demonstrating that DUF4297–HerA confers resistance against phage infection by cooperatively cleaving dsDNA and hydrolyzing ATP. DUF4297 alone forms a dimer, and HerA alone exists as a nonplanar split spiral hexamer, both of which exhibit extremely low enzymatic activity. Interestingly, DUF4297 and HerA assemble into an approximately 1 MDa supramolecular complex, where two layers of DUF4297 (6 DUF4297 molecules per layer) linked via inter-layer dimerization of neighboring DUF4297 molecules are stacked on top of the HerA hexamer. Importantly, the complex assembly promotes dimerization of DUF4297 molecules in the upper layer and enables a transition of HerA from a nonplanar hexamer to a planar hexamer, thus activating their respective enzymatic activities to abrogate phage infection. Together, our findings not only characterize a novel dual-enzyme anti-phage defense system, but also reveal a unique activation mechanism by cooperative complex assembly in bacterial immunity.
{"title":"Molecular and structural basis of an ATPase-nuclease dual-enzyme anti-phage defense complex","authors":"Qiyin An, Yong Wang, Zhenhua Tian, Jie Han, Jinyue Li, Fumeng Liao, Feiyang Yu, Haiyan Zhao, Yancheng Wen, Heng Zhang, Zengqin Deng","doi":"10.1038/s41422-024-00981-w","DOIUrl":"10.1038/s41422-024-00981-w","url":null,"abstract":"Coupling distinct enzymatic effectors emerges as an efficient strategy for defense against phage infection in bacterial immune responses, such as the widely studied nuclease and cyclase activities in the type III CRISPR-Cas system. However, concerted enzymatic activities in other bacterial defense systems are poorly understood. Here, we biochemically and structurally characterize a two-component defense system DUF4297–HerA, demonstrating that DUF4297–HerA confers resistance against phage infection by cooperatively cleaving dsDNA and hydrolyzing ATP. DUF4297 alone forms a dimer, and HerA alone exists as a nonplanar split spiral hexamer, both of which exhibit extremely low enzymatic activity. Interestingly, DUF4297 and HerA assemble into an approximately 1 MDa supramolecular complex, where two layers of DUF4297 (6 DUF4297 molecules per layer) linked via inter-layer dimerization of neighboring DUF4297 molecules are stacked on top of the HerA hexamer. Importantly, the complex assembly promotes dimerization of DUF4297 molecules in the upper layer and enables a transition of HerA from a nonplanar hexamer to a planar hexamer, thus activating their respective enzymatic activities to abrogate phage infection. Together, our findings not only characterize a novel dual-enzyme anti-phage defense system, but also reveal a unique activation mechanism by cooperative complex assembly in bacterial immunity.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247608","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}