Succination inactivates gasdermin D and blocks pyroptosis

TLDR

Activated macrophages shift to aerobic glycolysis, accumulating Krebs cycle intermediates that modulate immune gene transcription. The study seeks to establish fumarate as an inhibitor of pyroptotic cell death. Dimethyl fumarate and endogenous fumarate succinate gasdermin D at key cysteines, preventing its caspase interaction, processing, oligomerization, and pyroptotic activity; in mice, DMF protects against LPS shock and improves familial Mediterranean fever and experimental autoimmune encephalitis by targeting GSDMD, revealing fumarate as a therapeutic target for multiple sclerosis.

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.