Caspase-8-dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality.
- Demarco B Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
- Grayczyk JP Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA.
- Bjanes E Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA. kaiwen.chen@nus.edu.sg petr.broz@unil.ch.
- Le Roy D Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Epalinges, Switzerland.
- Tonnus W Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
- Assenmacher CA Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA.
- Radaelli E Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA.
- Fettrelet T Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
- Mack V Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
- Linkermann A Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
- Roger T Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Epalinges, Switzerland.
- Brodsky IE Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA.
- Chen KW Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland. kaiwen.chen@nus.edu.sg petr.broz@unil.ch.
- Broz P Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland. kaiwen.chen@nus.edu.sg petr.broz@unil.ch.
- 2020-11-19
Published in:
- Science advances. - 2020
English
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.
- Language
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- English
- Open access status
- gold
- Identifiers
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- DOI 10.1126/sciadv.abc3465
- PMID 33208362
- Persistent URL
- https://sonar.ch/global/documents/1573
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