| First Author | Xu W | Year | 2021 |
| Journal | Cell Metab | Volume | 33 |
| Issue | 2 | Pages | 424-436.e10 |
| PubMed ID | 33308446 | Mgi Jnum | J:325178 |
| Mgi Id | MGI:6510378 | Doi | 10.1016/j.cmet.2020.11.018 |
| Citation | Xu W, et al. (2021) Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition. Cell Metab 33(2):424-436.e10 |
| abstractText | 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. |
