首页 > 最新文献

Cell Research最新文献

英文 中文
Localized, highly efficient secretion of signaling proteins by migrasomes 迁移体局部高效分泌信号蛋白
IF 28.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-25 DOI: 10.1038/s41422-024-00992-7
Haifeng Jiao, Xiaopeng Li, Ying Li, Yuting Guo, Xiaoyu Hu, Takami Sho, Yiqun Luo, Jinyu Wang, Huizhen Cao, Wanqing Du, Dong Li, Li Yu
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.
移行体富含趋化因子、细胞因子和血管生成因子等信号分子,在这些分子的空间传递中发挥着关键作用,影响着器官形态发生和血管生成等关键生理过程。信号分子在移行体中的积累机制一直难以捉摸。在这项研究中,我们发现分泌蛋白(包括信号蛋白)通过组成型分泌途径和调节型分泌途径被分泌载体运输到迁移体中。在细胞迁移过程中,这些载体的很大一部分被重新定向到细胞后部,并在肌动蛋白依赖性马达蛋白肌球蛋白-5a的驱动下被主动运输到迁移体中。一旦进入移行体,这些载体就会通过 SNARE 介导的机制与移行体膜融合。抑制迁移体的形成可显著减少分泌,这表明迁移体是迁移细胞的主要分泌途径。我们的研究结果揭示了迁移细胞中一种专门的、高度局部化的分泌模式,在概念上与神经元系统中观察到的定向神经递质释放相似。
{"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}
引用次数: 0
ANT2: the first mammalian mitochondrial RNA transport translocon ANT2:第一个哺乳动物线粒体 RNA 转运易位子
IF 28.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-24 DOI: 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}
引用次数: 0
Combination therapy of KRAS G12V mRNA vaccine and pembrolizumab: clinical benefit in patients with advanced solid tumors KRAS G12V mRNA疫苗与pembrolizumab的联合疗法:晚期实体瘤患者的临床获益。
IF 28.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-24 DOI: 10.1038/s41422-024-00990-9
Xinjing Wang, Wei Wang, Siyi Zou, Zhiwei Xu, Dan Cao, Shuai Zhang, Minzhi Wei, Qian Zhan, Chenlei Wen, Fanlu Li, Hao Chen, Da Fu, Lingxi Jiang, Ming Zhao, Baiyong Shen
{"title":"Combination therapy of KRAS G12V mRNA vaccine and pembrolizumab: clinical benefit in patients with advanced solid tumors","authors":"Xinjing Wang, Wei Wang, Siyi Zou, Zhiwei Xu, Dan Cao, Shuai Zhang, Minzhi Wei, Qian Zhan, Chenlei Wen, Fanlu Li, Hao Chen, Da Fu, Lingxi Jiang, Ming Zhao, Baiyong Shen","doi":"10.1038/s41422-024-00990-9","DOIUrl":"10.1038/s41422-024-00990-9","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/s41422-024-00990-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445717","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}
引用次数: 0
AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine AMPK 以 PDZD8 为靶标,触发碳源从葡萄糖向谷氨酰胺的转移。
IF 28.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-19 DOI: 10.1038/s41422-024-00985-6
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
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.
碳的利用从主要利用葡萄糖转向利用其他营养物质,是应对血糖水平下降和随之而来的葡萄糖氧化下降的一种基本代谢适应。AMP 激活蛋白激酶(AMPK)在这种新陈代谢适应中起着至关重要的作用。然而,其潜在机制尚未完全明了。在这里,我们发现,PDZ 含域 8(PDZD8)是 AMPK 在低糖条件下激活的新底物,它是低糖促进谷氨酰胺溶解所必需的。AMPK 使 PDZD8 在苏氨酸 527 (T527) 处磷酸化,并促进 PDZD8 与谷氨酰胺酶 1 (GLS1) 的相互作用和激活,GLS1 是谷氨酰胺分解的限速酶。在体内,AMPK-PDZD8-GLS1 轴是增强谷氨酰胺酵解所必需的,骨骼肌组织的测试结果表明,谷氨酰胺酵解的增强早于禁食期间脂肪酸利用的增加。在低糖或急性脂多糖(LPS)处理下的巨噬细胞中也能观察到谷氨酰胺溶解的增强。PDZD8-T527A 突变抑制了经 LPS 处理的小鼠巨噬细胞中促炎细胞因子的分泌,这与谷氨酰胺分解增强的要求相一致。综上所述,我们揭示了 AMPK-PDZD8-GLS1 轴在葡萄糖不足的情况下促进谷氨酰胺酵解,而不是增加脂肪酸的利用。
{"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}
引用次数: 0
Pyroptosis: palmitoylation regulates GSDMD activation and pore formation 裂解:棕榈酰化调节 GSDMD 的激活和孔隙形成
IF 28.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-18 DOI: 10.1038/s41422-024-00988-3
Ella Hartenian, Petr Broz
{"title":"Pyroptosis: palmitoylation regulates GSDMD activation and pore formation","authors":"Ella Hartenian, Petr Broz","doi":"10.1038/s41422-024-00988-3","DOIUrl":"10.1038/s41422-024-00988-3","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-00988-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141334183","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}
引用次数: 0
AI accurately predicting the structure of biomolecular interactions 人工智能准确预测生物分子相互作用的结构。
IF 28.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-14 DOI: 10.1038/s41422-024-00991-8
Zhenling Peng, Peilong Lu, Jianyi Yang
{"title":"AI accurately predicting the structure of biomolecular interactions","authors":"Zhenling Peng, Peilong Lu, Jianyi Yang","doi":"10.1038/s41422-024-00991-8","DOIUrl":"10.1038/s41422-024-00991-8","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-00991-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141320655","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}
引用次数: 0
Structural insights into VAChT neurotransmitter recognition and inhibition 有关 VAChT 神经递质识别和抑制的结构见解
IF 28.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-11 DOI: 10.1038/s41422-024-00986-5
Yang Zhang, Fei Dai, Nanhao Chen, Dong Zhou, Chia-Hsueh Lee, Chen Song, Yixiao Zhang, Zhe Zhang
{"title":"Structural insights into VAChT neurotransmitter recognition and inhibition","authors":"Yang Zhang, Fei Dai, Nanhao Chen, Dong Zhou, Chia-Hsueh Lee, Chen Song, Yixiao Zhang, Zhe Zhang","doi":"10.1038/s41422-024-00986-5","DOIUrl":"10.1038/s41422-024-00986-5","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-00986-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141304451","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}
引用次数: 0
Tumor microenvironment squeezes out the juice from T cells 肿瘤微环境榨干了 T 细胞的汁液
IF 28.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-10 DOI: 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}
引用次数: 0
A GABAergic system in atrioventricular node pacemaker cells controls electrical conduction between the atria and ventricles 房室结起搏细胞中的 GABA 能系统控制着心房和心室之间的电传导
IF 28.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-07 DOI: 10.1038/s41422-024-00980-x
Dandan Liang, Liping Zhou, Huixing Zhou, Fulei Zhang, Guojian Fang, Junwei Leng, Yahan Wu, Yuemei Zhang, Anqi Yang, Yi Liu, Yi-Han Chen
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.
生理学上,心房先收缩,心室后收缩,这是正常血液循环的前提条件。上述房室顺序收缩的现象是由于房室结(AVN)的电兴奋在心房和心室之间的传导速度非常缓慢。然而,目前还不清楚是什么控制着房室结内电兴奋的传导。在这里,我们发现房室结起搏细胞(AVNPCs)具有完整的内在 GABA 能系统,它在从心房到心室的电传导中起着关键作用。首先,随着在 AVNPCs 表膜下发现大量含 GABA 的囊泡,GABA 能系统的关键元素,包括 GABA 代谢酶、GABA 受体和 GABA 转运体也在 AVNPCs 中被确定。其次,GABA 可同步激发 AVNPCs 中的 GABA 门控电流,从而显著削弱 AVNPCs 的兴奋性。第三,GABA能系统的关键分子元素明显调节了房室神经元电兴奋的传导性。第四,房室神经元中 GABAA 受体的缺乏会加速房室传导,从而损害房室神经元对快速心室频率响应的保护潜能,增加对致命性室性心律失常的易感性,并降低心脏收缩功能。最后,针对 GABA 能系统的干预措施可有效防止房室传导阻滞的发生和发展。总之,房室神经元中的内源性 GABA 能系统决定了房室神经元内电兴奋的缓慢传导,从而确保了房室收缩的连续性。内源性 GABA 能系统有望成为心律失常的新型干预目标。
{"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}
引用次数: 0
Molecular and structural basis of an ATPase-nuclease dual-enzyme anti-phage defense complex ATP酶-核酸酶双酶抗噬菌体防御复合物的分子和结构基础。
IF 28.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-04 DOI: 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.
在细菌免疫反应中,将不同的酶效应器耦合在一起是抵御噬菌体感染的有效策略,例如被广泛研究的 III 型 CRISPR-Cas 系统中的核酸酶和环化酶活动。然而,人们对其他细菌防御系统中的协同酶活性知之甚少。在这里,我们从生物化学和结构上描述了双组分防御系统 DUF4297-HerA,证明 DUF4297-HerA 通过协同裂解 dsDNA 和水解 ATP 来抵抗噬菌体感染。DUF4297 单独形成二聚体,而 HerA 单独以非平面分裂螺旋六聚体的形式存在,两者都表现出极低的酶活性。有趣的是,DUF4297 和 HerA 组装成一个约 1 MDa 的超分子复合物,其中两层 DUF4297(每层 6 个 DUF4297 分子)通过相邻 DUF4297 分子的层间二聚化连接在一起,堆叠在 HerA 六聚体的顶部。重要的是,复合体的组装促进了上层 DUF4297 分子的二聚化,并使 HerA 从非平面六聚体转变为平面六聚体,从而激活了它们各自的酶活性,以抑制噬菌体感染。总之,我们的研究结果不仅描述了一种新型双酶抗噬菌体防御系统的特征,而且揭示了细菌免疫中通过合作复合物组装的独特激活机制。
{"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}
引用次数: 0
期刊
Cell Research
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1