RT Journal Article
SR Electronic
T1 Caspase-8–dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality
JF Science Advances
JO Sci Adv
FD American Association for the Advancement of Science
SP eabc3465
DO 10.1126/sciadv.abc3465
VO 6
IS 47
A1 Demarco, Benjamin
A1 Grayczyk, James P.
A1 Bjanes, Elisabet
A1 Le Roy, Didier
A1 Tonnus, Wulf
A1 Assenmacher, Charles-Antoine
A1 Radaelli, Enrico
A1 Fettrelet, Timothée
A1 Mack, Vanessa
A1 Linkermann, Andreas
A1 Roger, Thierry
A1 Brodsky, Igor E.
A1 Chen, Kaiwen W.
A1 Broz, Petr
YR 2020
UL http://advances.sciencemag.org/content/6/47/eabc3465.abstract
AB 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.