Caspase-8-dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality.

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Version: Final published version
License: CC BY-NC 4.0
Serval ID
serval:BIB_1DC0C3FF12E6
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Caspase-8-dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality.
Journal
Science advances
Author(s)
Demarco B., Grayczyk J.P., Bjanes E., Le Roy D., Tonnus W., Assenmacher C.A., Radaelli E., Fettrelet T., Mack V., Linkermann A., Roger T., Brodsky I.E., Chen K.W., Broz P.
ISSN
2375-2548 (Electronic)
ISSN-L
2375-2548
Publication state
Published
Issued date
11/2020
Peer-reviewed
Oui
Volume
6
Number
47
Pages
eabc3465
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
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.
Pubmed
Web of science
Open Access
Yes
Funding(s)
Swiss National Science Foundation
Swiss National Science Foundation
Create date
19/11/2020 15:35
Last modification date
30/04/2021 7:08
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