Succination inactivates gasdermin D and blocks pyroptosis

• Published in: Science (American Association for the Advancement of Science) 2020-09, Vol.369 (6511), p.1633-1637
• 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: Article
• Language: English
• Subjects: Animal models; Animals; Anti-inflammatory agents; Apoptosis; Caspase; Caspases - metabolism; Cell death; Citric Acid Cycle - drug effects; Cysteine; Cysteine - analogs & derivatives; Cysteine - metabolism; Dimethyl Fumarate - pharmacology; Dimethyl Fumarate - therapeutic use; Drug development; Encephalitis; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Experimental allergic encephalomyelitis; Familial Mediterranean fever; Familial Mediterranean Fever - drug therapy; Female; Fever; Glycolysis; HEK293 Cells; Humans; Immune response; Inflammasomes - drug effects; Inflammasomes - metabolism; Inflammatory diseases; Intermediates; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Lipopolysaccharides; Lipopolysaccharides - immunology; Macrophage Activation; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Male; Medical treatment; Membrane permeability; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mortality; Multiple sclerosis; Multiple Sclerosis - drug therapy; Oligomerization; Phosphate-Binding Proteins - genetics; Phosphate-Binding Proteins - metabolism; Protein Processing, Post-Translational; Pyroptosis; Pyroptosis - drug effects; Pyroptosis - immunology; Target recognition; Transcription; Tricarboxylic acid cycle
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abb9818

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.