上睑下垂
线粒体通透性转换孔
半胱氨酸蛋白酶
细胞生物学
胞浆
生物
线粒体
半胱氨酸蛋白酶8
细胞色素c
NLRP1
化学
程序性细胞死亡
细胞凋亡
生物化学
酶
作者
Wanfeng Xu,Yuan Che,Quan Zhang,Hai Huang,Chujie Ding,Yun Wang,Guangji Wang,Lijuan Cao,Haiping Hao
出处
期刊:Cell Metabolism
[Elsevier]
日期:2021-02-01
卷期号:33 (2): 424-436.e10
被引量:72
标识
DOI:10.1016/j.cmet.2020.11.018
摘要
Caspase-4 is an intracellular sensor for cytosolic bacterial lipopolysaccharide (LPS) and underlies infection-elicited pyroptosis. It is unclear whether and how caspase-4 detects host-derived factors to trigger pyroptosis. Here we show that mitochondrial permeability transition (MPT) activates caspase-4 by promoting the assembly of a protein complex, which we term the Apaf-1 pyroptosome, for the execution of facilitated pyroptosis. MPT, when induced by bile acids, calcium overload, or an adenine nucleotide translocator 1 (ANT1) activator, triggers assembly of the pyroptosome comprised of Apaf-1 and caspase-4 with a stoichiometry ratio of 7:2. Unlike the direct cleavage of gasdermin D (GSDMD) by caspase-4 upon LPS ligation, caspase-4 activated in the Apaf-1 pyroptosome proceeds to cleave caspase-3 and thereby GSDME to induce pyroptosis. Caspase-4-initiated and GSDME-executed pyroptosis underlies cholestatic liver failure. These findings identify Apaf-1 pyroptosome as a pivotal machinery for cells sensing MPT signals and may shed light on understanding how cells execute intrinsic pyroptosis under sterile conditions.
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