Succination inactivates gasdermin D and blocks pyroptosis
Copyright policy )Succination inactivates gasdermin D and blocks pyroptosis
Fumarate targets pyroptosis A form of inflammatory cell death called pyroptosis depends on the caspase-mediated cleavage of gasdermin D (GSDMD), the fragments of which assemble into permeability pores that then kill the cell. The mechanisms regulating this important cellular process are not yet fully understood. Humphries et al. now report that the tricarboxylic acid cycle intermediate fumarate can act as an inhibitor of pyroptosis (see the Perspective by Pickering and Bryant). Both endogenous fumarate and exogenously delivered dimethyl fumarate (DMF) convert the cysteines in GSDMD to S-(2-succinyl)-cysteines (a process called succination) to prevent its interaction with caspases and subsequent processing and activation. Administration of DMF to mice alleviated inflammation in models of multiple sclerosis and familial Mediterranean fever. These findings may explain the efficacy of DMF as a treatment for multiple sclerosis and other inflammatory diseases and offer insights into future anti-inflammatory drug design. Science , this issue p. 1633 ; see also p. 1564
- GlaxoSmithKline (United States) United States
- Cellzome, GSK, Middlesex, UK.
- Cleveland Clinic United States
- University of Massachusetts Medical School United States
- Cleveland Clinic
Lipopolysaccharides, Male, 570, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, Biochemical Phenomena, Inflammasomes, Dimethyl Fumarate, Citric Acid Cycle, Biochemistry, Congenital, Mice, Enzymes and Coenzymes, 616, Animals, Humans, Cysteine, and Nutrition, Immunology and Infectious Disease, Macrophages, Intracellular Signaling Peptides and Proteins, Macrophage Activation, Mice, Mutant Strains, Familial Mediterranean Fever, Mice, Inbred C57BL, Metabolism, Hereditary, HEK293 Cells, Neurology, Caspases, Female, Nervous System Diseases, and Neonatal Diseases and Abnormalities
Lipopolysaccharides, Male, 570, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, Biochemical Phenomena, Inflammasomes, Dimethyl Fumarate, Citric Acid Cycle, Biochemistry, Congenital, Mice, Enzymes and Coenzymes, 616, Animals, Humans, Cysteine, and Nutrition, Immunology and Infectious Disease, Macrophages, Intracellular Signaling Peptides and Proteins, Macrophage Activation, Mice, Mutant Strains, Familial Mediterranean Fever, Mice, Inbred C57BL, Metabolism, Hereditary, HEK293 Cells, Neurology, Caspases, Female, Nervous System Diseases, and Neonatal Diseases and Abnormalities
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