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
  • 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: [email protected].
  • 3. State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing, China. Electronic address: [email protected].
PMID: 33308446 DOI: 10.1016/j.cmet.2020.11.018
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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