2. Academic Validation
  3. Succination inactivates gasdermin D and blocks pyroptosis

Succination inactivates gasdermin D and blocks pyroptosis

  • Science. 2020 Sep 25;369(6511):1633-1637. doi: 10.1126/science.abb9818.
Fiachra Humphries 1,  Liraz Shmuel-Galia 1,  Natalia Ketelut-Carneiro 1,  Sheng Li 2,  Bingwei Wang 3,  Venkatesh V Nemmara 4,  Ruth Wilson 1,  Zhaozhao Jiang 1,  Farnaz Khalighinejad 5,  Khaja Muneeruddin 6 7,  Scott A Shaffer 6 7,  Ranjan Dutta 8,  Carolina Ionete 5,  Scott Pesiridis 9,  Shuo Yang 2,  Paul R Thompson 7,  Katherine A Fitzgerald 10
Affiliations

Affiliations

  • 1 Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • 2 Department of Immunology, Key Laboratory of Immunological Environment and Disease, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
  • 3 Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, China.
  • 4 Department of Chemistry and Biochemistry, Rowan University, Glassboro, NJ 08028, USA.
  • 5 Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • 6 Mass Spectrometry Facility, University of Massachusetts Medical School, Shrewsbury, MA 01545, USA.
  • 7 Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • 8 Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Case Western Reserve University, Cleveland, OH 44106, USA.
  • 9 Innate Immunity Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • 10 Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. kate.fitzgerald@umassmed.edu.
PMID: 32820063 DOI: 10.1126/science.abb9818
Abstract

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.

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