Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition

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.