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

Science Advances
Benjamin DemarcoPetr Broz

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.

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Citations

Feb 27, 2021·Frontiers in Cell and Developmental Biology·Man WangYuan Zhang
Mar 12, 2021·Nature Reviews. Drug Discovery·Xing LiuJudy Lieberman
Mar 28, 2021·Trends in Cell Biology·Elke De SchutterPeter Vandenabeele
Mar 23, 2021·Biochimie·Xiaoli JuQiang Wang
Apr 4, 2021·International Journal of Molecular Sciences·Jun-Hyuk HanKwang-Ho Lee
Apr 29, 2021·Trends in Immunology·Daolin TangRui Kang
Apr 20, 2021·Frontiers in Immunology·Fabian A FischerJelena S Bezbradica
May 20, 2021·Oxidative Medicine and Cellular Longevity·Ke-Jia ZhangLi Li
Jul 22, 2021·Trends in Cell Biology·Abhimanu PandeySi Ming Man
Jul 15, 2021·Proceedings of the National Academy of Sciences of the United States of America·Kaiwen W ChenPetr Broz
Aug 8, 2021·International Journal of Molecular Sciences·Sonia EmanueleMichela Giuliano
Aug 26, 2021·Journal of Experimental & Clinical Cancer Research : CR·Reid LovelessYong Teng
Aug 24, 2021·Current Opinion in Immunology·Margaret M McDanielChandrashekhar Pasare
Oct 1, 2021·Cell Proliferation·Tong LiLipeng Tang
Sep 20, 2021·Journal of Molecular Biology·Sebastian Rühl, Petr Broz
Oct 11, 2021·Journal of Molecular Biology·Madeline J ChurchillIsabella Rauch
Nov 11, 2021·Journal of Molecular Biology·Gabriel Sollberger

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