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Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition.

Cell metabolism (2020-12-15)
Wanfeng Xu, Yuan Che, Quan Zhang, Hai Huang, Chujie Ding, Yun Wang, Guangji Wang, Lijuan Cao, Haiping Hao
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
ARL 67156 trisodium salt hydrate, ≥98% (HPLC), solid
Sigma-Aldrich
Phorbol 12-myristate 13-acetate, ≥99% (TLC), film or powder
Sigma-Aldrich
Protease Inhibitor Cocktail, for use with mammalian cell and tissue extracts, DMSO solution
Supelco
Protein Standard Mix 15 - 600 kDa, for size exclusion chromatography