Succination inactivates gasdermin D and blocks pyroptosis

Activated macrophages undergo a metabolic switch to aerobic glycolysis, accumulating Krebs' cycle intermediates that alter transcription of immune response genes. We extended these observations by defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF)...

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Bibliographic Details
Published in:	Science (American Association for the Advancement of Science) Vol. 369; no. 6511; p. 1633
Main Authors:	Humphries, Fiachra, Shmuel-Galia, Liraz, Ketelut-Carneiro, Natalia, Li, Sheng, Wang, Bingwei, Nemmara, Venkatesh V, Wilson, Ruth, Jiang, Zhaozhao, Khalighinejad, Farnaz, Muneeruddin, Khaja, Shaffer, Scott A, Dutta, Ranjan, Ionete, Carolina, Pesiridis, Scott, Yang, Shuo, Thompson, Paul R, Fitzgerald, Katherine A
Format:	Journal Article
Language:	English
Published:	United States 25.09.2020
Subjects:	Animals Caspases - metabolism Citric Acid Cycle - drug effects Cysteine - analogs & derivatives Cysteine - metabolism Dimethyl Fumarate - pharmacology Dimethyl Fumarate - therapeutic use Encephalomyelitis, Autoimmune, Experimental - drug therapy Familial Mediterranean Fever - drug therapy Female HEK293 Cells Humans Inflammasomes - drug effects Inflammasomes - metabolism Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism Lipopolysaccharides - immunology Macrophage Activation Macrophages - drug effects Macrophages - immunology Macrophages - metabolism Male Mice Mice, Inbred C57BL Mice, Mutant Strains Multiple Sclerosis - drug therapy Phosphate-Binding Proteins - genetics Phosphate-Binding Proteins - metabolism Protein Processing, Post-Translational Pyroptosis - drug effects Pyroptosis - immunology
ISSN:	1095-9203, 1095-9203
Online Access:	Get more information
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Summary:	Activated macrophages undergo a metabolic switch to aerobic glycolysis, accumulating Krebs' cycle intermediates that alter transcription of immune response genes. We extended these observations by defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF) delivered to cells or endogenous fumarate reacts with gasdermin D (GSDMD) at critical cysteine residues to form S-(2-succinyl)-cysteine. GSDMD succination prevents its interaction with caspases, limiting its processing, oligomerization, and capacity to induce cell death. In mice, the administration of DMF protects against lipopolysaccharide shock and alleviates familial Mediterranean fever and experimental autoimmune encephalitis by targeting GSDMD. Collectively, these findings identify GSDMD as a target of fumarate and reveal a mechanism of action for fumarate-based therapeutics that include DMF, for the treatment of multiple sclerosis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1095-9203 1095-9203
DOI:	10.1126/science.abb9818