PT  - JOURNAL ARTICLE
AU  - Rosalie Heilig
AU  - Marisa Dilucca
AU  - Dave Boucher
AU  - Kaiwen W Chen
AU  - Dora Hancz
AU  - Benjamin Demarco
AU  - Kateryna Shkarina
AU  - Petr Broz
TI  - Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD
AID  - 10.26508/lsa.202000735
DP  - 2020 Jun 01
TA  - Life Science Alliance
PG  - e202000735
VI  - 3
IP  - 6
4099  - https://www.life-science-alliance.org/content/3/6/e202000735.short
4100  - https://www.life-science-alliance.org/content/3/6/e202000735.full
SO  - Life Sci. Alliance2020 Jun 01; 3
AB  - Caspase-1 drives a lytic inflammatory cell death named pyroptosis by cleaving the pore-forming cell death executor gasdermin-D (GSDMD). Gsdmd deficiency, however, only delays cell lysis, indicating that caspase-1 controls alternative cell death pathways. Here, we show that in the absence of GSDMD, caspase-1 activates apoptotic initiator and executioner caspases and triggers a rapid progression into secondary necrosis. GSDMD-independent cell death required direct caspase-1–driven truncation of Bid and generation of caspase-3 p19/p12 by either caspase-8 or caspase-9. tBid-induced mitochondrial outer membrane permeabilization was also required to drive SMAC release and relieve inhibitor of apoptosis protein inhibition of caspase-3, thereby allowing caspase-3 auto-processing to the fully active p17/p12 form. Our data reveal that cell lysis in inflammasome-activated Gsdmd-deficient cells is caused by a synergistic effect of rapid caspase-1–driven activation of initiator caspases-8/-9 and Bid cleavage, resulting in an unusually fast activation of caspase-3 and immediate transition into secondary necrosis. This pathway might be advantageous for the host in counteracting pathogen-induced inhibition of GSDMD but also has implications for the use of GSDMD inhibitors in immune therapies for caspase-1–dependent inflammatory disease.