PT  - JOURNAL ARTICLE
AU  - Wanfeng Xu
AU  - Yuan Che
AU  - Quan Zhang
AU  - Hai Huang
AU  - Chujie Ding
AU  - Yun Wang
AU  - Guangji Wang
AU  - Lijuan Cao
AU  - Haiping Hao
TI  - Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition
AID  - 10.1101/2020.01.27.921122
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.27.921122
4099  - http://biorxiv.org/content/early/2020/01/28/2020.01.27.921122.short
4100  - http://biorxiv.org/content/early/2020/01/28/2020.01.27.921122.full
AB  - Caspase-4 directly senses and is activated by cytosolic LPS in conditions of pathogen infection. It is unclear whether and how caspase-4 detects host derived factors for triggering pyroptosis. Here we show that mitochondrial permeability transition (MPT) promotes the assembly of a protein complex comprised of Apaf-1 and caspase-4 (caspase-11 in mice), defined herein as pyroptosome, for the execution of facilitated pyroptosis. MPT induced by bile acids and calcium overload, and specifically by an adenine nucleotide translocator 1 (ANT1) activator, triggered pyroptosome assembly. Different from the direct cleavage of GSDMD by LPS-activated caspase-4, caspase-4 activated in the Apaf-1 pyroptosome proceeds to cleave caspase-3 and thereby gasdermin E (GSDME) to induce pyroptosis. Caspase-11 initiated and GSDME executed pyroptosis underlies cholesteric liver failure. These findings identify Apaf-1 pyroptosome as a pivotal machinery for cells sensing MPT signals and may shed lights on understanding how cells execute pyroptosis under sterile conditions.HighlightsBile acids trigger caspase-4/11 and GSDME dependent pyroptosisCaspase-4/11 is a general sensor of mitochondrial permeability transition (MPT)MPT drives Apaf-1/capase-4 pryoptosome assemblyCaspase-11 and GSDME mediated pyroptosis underlies cholesteric liver damageeTOC Blurb Persistent mitochondrial permeability transition elicited by bile acids, calcium overload and specifically ANT1 activators drives assembly of Apaf-1-capase-4/11 pyroptosome triggering GSDME dependent pryroptosis.