Succination inactivates gasdermin D and blocks pyroptosis

Author:

Humphries Fiachra1ORCID,Shmuel-Galia Liraz1,Ketelut-Carneiro Natalia1ORCID,Li Sheng2,Wang Bingwei3ORCID,Nemmara Venkatesh V.4ORCID,Wilson Ruth1,Jiang Zhaozhao1,Khalighinejad Farnaz5,Muneeruddin Khaja67,Shaffer Scott A.67ORCID,Dutta Ranjan8ORCID,Ionete Carolina5,Pesiridis Scott9,Yang Shuo2ORCID,Thompson Paul R.7ORCID,Fitzgerald Katherine A.1ORCID

Affiliation:

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.

Abstract

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

Funder

National Institutes of Health

Worcester Foundation

Dan and Diane Riccio Fund for Neuroscience

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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