PT - JOURNAL ARTICLE AU - Heilig, Rosalie AU - Dilucca, Marisa AU - Boucher, Dave AU - Chen, Kaiwen W AU - Hancz, Dora AU - Demarco, Benjamin AU - Shkarina, Kateryna AU - Broz, Petr 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 - http://www.life-science-alliance.org/content/3/6/e202000735.short 4100 - http://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.