Succination inactivates gasdermin D and blocks pyroptosis
Program in Innate Immunity, Department of Medicine, Division of Infectious Diseases and Immunology; Department of Neurology; Mass Spectrometry Facility; Department of Biochemistry and Molecular Pharmacology; Thompson Lab
Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Enzymes and Coenzymes | Immunology and Infectious Disease | Nervous System Diseases | Neurology
Activated macrophages undergo a metabolic switch to aerobic glycolysis accumulating Krebs cycle intermediates that alter transcription of immune response genes. Here we extend 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 LPS shock and alleviates familial Mediterranean fever and experimental autoimmune encephalitis (EAE) by targeting GSDMD. Collectively, these findings identify GSDMD as a target of fumarate and reveal a mechanism of action for fumarate-based therapeutics including DMF used to treat multiple sclerosis.
DOI of Published Version
Humphries F, Shmuel-Galia L, Ketelut-Carneiro N, Li S, Wang B, Nemmara VV, Wilson R, Jiang Z, Khalighinejad F, Muneeruddin K, Shaffer SA, Dutta R, Ionete C, Pesiridis S, Yang S, Thompson PR, Fitzgerald KA. Succination inactivates gasdermin D and blocks pyroptosis. Science. 2020 Sep 25;369(6511):1633-1637. doi: 10.1126/science.abb9818. Epub 2020 Aug 20. PMID: 32820063. Link to article on publisher's site
Science (New York, N.Y.)
Humphries F, Shmuel-Galia L, Ketelut-Carneiro N, Wilson R, Jiang Z, Khalighinejad F, Muneeruddin K, Shaffer SA, Ionete C, Thompson PR, Fitzgerald KA. (2020). Succination inactivates gasdermin D and blocks pyroptosis. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1126/science.abb9818. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1811