1. Academic Validation
  2. Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition

Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition

  • Cell Metab. 2021 Feb 2;33(2):424-436.e10. doi: 10.1016/j.cmet.2020.11.018.
Wanfeng Xu 1 Yuan Che 1 Quan Zhang 1 Hai Huang 1 Chujie Ding 1 Yun Wang 1 Guangji Wang 1 Lijuan Cao 2 Haiping Hao 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing, China.
  • 2 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing, China. Electronic address: caolijuan0702@cpu.edu.cn.
  • 3 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing, China. Electronic address: haipinghao@cpu.edu.cn.
Abstract

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.

Keywords

Apaf-1; Caspase-4; bile acid; gasdermin E; mitochondrial permeability transition; pyroptosis.

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