Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell   death

doi:10.1038/nature15514

CORC > 北京大学 > 生命科学学院

	Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death
	Shi, Jianjin ; Zhao, Yue ; Wang, Kun ; Shi, Xuyan ; Wang, Yue ; Huang, Huanwei ; Zhuang, Yinghua ; Cai, Tao ; Wang, Fengchao ; Shao, Feng
刊名	NATURE
	2015
关键词	III SECRETION APPARATUS BACTERIAL FLAGELLIN NLRC4 INFLAMMASOME INTRACELLULAR LPS ACTIVATION MECHANISMS RECEPTORS IMMUNITY
DOI	10.1038/nature15514
英文摘要	Inflammatory caspases (caspase-1, -4, -5 and -11) are critical for innate defences. Caspase-1 is activated by ligands of various canonical inflammasomes, and caspase-4, -5 and -11 directly recognize bacterial lipopolysaccharide, both of which trigger pyroptosis. Despite the crucial role in immunity and endotoxic shock, the mechanism for pyroptosis induction by inflammatory caspases is unknown. Here we identify gasdermin D (Gsdmd) by genome-wide clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 nuclease screens of caspase-11- and caspase-1-mediated pyroptosis in mouse bone marrow macrophages. GSDMD-deficient cells resisted the induction of pyroptosis by cytosolic lipopolysaccharide and known canonical inflammasome ligands. Interleukin-1 beta release was also diminished in Gsdmd(-/-) cells, despite intact processing by caspase-1. Caspase-1 and caspase-4/5/11 specifically cleaved the linker between the amino-terminal gasdermin-N and carboxy-terminal gasdermin-C domains in GSDMD, which was required and sufficient for pyroptosis. The cleavage released the intramolecular inhibition on the gasdermin-N domain that showed intrinsic pyroptosis-inducing activity. Other gasdermin family members were not cleaved by inflammatory caspases but shared the autoinhibition; gain-of-function mutations in Gsdma3 that cause alopecia and skin defects disrupted the autoinhibition, allowing its gasdermin-N domain to trigger pyroptosis. These findings offer insight into inflammasome-mediated immunity/diseases and also change our understanding of pyroptosis and programmed necrosis.; Chinese Academy of Sciences [XDB08020202]; China National Science Foundation Program for Distinguished Young Scholars [31225002]; Program for International Collaborations [31461143006]; National Basic Research Program of China 973 Program [2012CB518700, 2014CB849602]; Howard Hughes Medical Institute; Beijing Scholar Program; SCI(E); PubMed; ARTICLE; shaofeng@nibs.ac.cn; 7575; 660-665; 526
语种	英语
内容类型	期刊论文
源URL	[http://ir.pku.edu.cn/handle/20.500.11897/415548]
专题	生命科学学院
推荐引用方式 GB/T 7714	Shi, Jianjin,Zhao, Yue,Wang, Kun,et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death[J]. NATURE,2015.
APA	Shi, Jianjin.,Zhao, Yue.,Wang, Kun.,Shi, Xuyan.,Wang, Yue.,...&Shao, Feng.(2015).Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.NATURE.
MLA	Shi, Jianjin,et al."Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death".NATURE (2015).