1. Academic Validation
  2. Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD

Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD

  • Life Sci Alliance. 2020 Apr 28;3(6):e202000735. doi: 10.26508/lsa.202000735.
Rosalie Heilig 1 Marisa Dilucca 1 Dave Boucher 1 Kaiwen W Chen 1 Dora Hancz 1 Benjamin Demarco 1 Kateryna Shkarina 1 Petr Broz 2
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
  • 2 Department of Biochemistry, University of Lausanne, Epalinges, Switzerland petr.broz@unil.ch.
Abstract

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.

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