期刊
SCIENCE ADVANCES
卷 6, 期 47, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abc3465
关键词
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资金
- Marie Sklodowska-Curie Actions (MSCA) incoming fellowship [MSCA-IF-2018-838252]
- European Research Council [ERC2017-CoG-770988]
- Swiss National Science Foundation grant (SNSF) [310030_173123]
- NIH [1R21135421, 1R01128530]
- Burroughs Wellcome Fund Pathogenesis of Infectious Disease Award
- DFG [SFB-TRR 205, SFB-TRR 127]
- International Research Training Group (IRTG) [2251]
- Swiss National Science Foundation (SNF) [310030_173123] Funding Source: Swiss National Science Foundation (SNF)
Gasdermin D (GSDMD) is a pore-forming protein that promotes pyroptosis and release of proinflammatory cytokines. Recent studies revealed that apoptotic caspase-8 directly cleaves GSDMD to trigger pyroptosis. However, the molecular requirements for caspase-8-dependent GSDMD cleavage and the physiological impact of this signaling axis are unresolved. Here, we report that caspase-8-dependent GSDMD cleavage confers susceptibility to tumor necrosis factor (TNF)-induced lethality independently of caspase-1 and that GSDMD activation provides host defense against Yersinia infection. We further demonstrate that GSDMD inactivation by apoptotic caspases at aspartate 88 (D88) suppresses TNF-induced lethality but promotes anti-Yersinia defense. Last, we show that caspase-8 dimerization and autoprocessing are required for GSDMD cleavage, and provide evidence that the caspase-8 autoprocessing and activity on various complexes correlate with its ability to directly cleave GSDMD. These findings reveal GSDMD as a potential therapeutic target to reduce inflammation associated with mutations in the death receptor signaling machinery.
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