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https://doi.org/10.1126/sciadv.abc3465
Title: | Caspase-8-dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality | Authors: | Demarco, B. Grayczyk, J.P. Bjanes, E. Roy, D.L. Tonnus, W. Assenmacher, C.-A. Radaelli, E. Fettrelet, T. Mack, V. Linkermann, A. Roger, T. Brodsky, I.E. Chen, K.W. Broz, P. |
Issue Date: | 2020 | Publisher: | American Association for the Advancement of Science | Citation: | Demarco, B., Grayczyk, J.P., Bjanes, E., Roy, D.L., Tonnus, W., Assenmacher, C.-A., Radaelli, E., Fettrelet, T., Mack, V., Linkermann, A., Roger, T., Brodsky, I.E., Chen, K.W., Broz, P. (2020). Caspase-8-dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality. Science Advances 6 (47) : eabc3465. ScholarBank@NUS Repository. https://doi.org/10.1126/sciadv.abc3465 | Rights: | Attribution-NonCommercial 4.0 International | 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. Copyright c 2020 The Authors, some rights reserved;. | Source Title: | Science Advances | URI: | https://scholarbank.nus.edu.sg/handle/10635/199675 | ISSN: | 2375-2548 | DOI: | 10.1126/sciadv.abc3465 | Rights: | Attribution-NonCommercial 4.0 International |
Appears in Collections: | Elements Staff Publications |
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