Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD
| Autor: | Heilig, Rosalie, Dilucca, Marisa, Boucher, Dave, Chen, Kaiwen W, Hancz, Dora, Demarco, Benjamin, Shkarina, Kateryna, Broz, Petr |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Inflammasomes
Animals Apoptosis/genetics Apoptosis Regulatory Proteins/metabolism BH3 Interacting Domain Death Agonist Protein/deficiency BH3 Interacting Domain Death Agonist Protein/genetics Caspase 1/deficiency Caspase 1/genetics Cells Cultured Gene Editing Gene Knockout Techniques Inflammasomes/metabolism Intracellular Signaling Peptides and Proteins/deficiency Intracellular Signaling Peptides and Proteins/genetics Macrophages/metabolism Macrophages/pathology Mice Mice Inbred C57BL Mice Knockout Mitochondria/metabolism Mitochondrial Membranes/metabolism Mitochondrial Proteins/metabolism Necrosis/genetics Necrosis/metabolism Phosphate-Binding Proteins/deficiency Phosphate-Binding Proteins/genetics Pyroptosis/genetics Signal Transduction/genetics Transfection Apoptosis Mitochondrial Proteins Necrosis Pyroptosis Research Articles Macrophages Caspase 1 Intracellular Signaling Peptides and Proteins Phosphate-Binding Proteins Mitochondria Mitochondrial Membranes biological phenomena cell phenomena and immunity Apoptosis Regulatory Proteins BH3 Interacting Domain Death Agonist Protein Signal Transduction Research Article |
| Zdroj: | Life science alliance, vol. 3, no. 6, pp. e202000735 Life Science Alliance |
| ISSN: | 2575-1077 |
| Popis: | Caspase-1 activation in GSDMD-deficient cells induces a rapid form of caspase-3–dependent secondary necrosis that is licenced by caspase-1–induced Bid cleavage and the release of mitochondrial SMAC. 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. |
| Databáze: | OpenAIRE |
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