Succination inactivates gasdermin D and blocks pyroptosis

Area of Science:

• Immunology
• Cellular Metabolism
• Molecular Biology

Background:

• Activated macrophages exhibit metabolic shifts towards aerobic glycolysis, influencing immune gene expression via Krebs cycle intermediates.
• Pyroptosis, a pro-inflammatory programmed cell death, is implicated in various inflammatory conditions.

Purpose of the Study:

• To investigate the role of fumarate in pyroptotic cell death.
• To identify the molecular target of fumarate in regulating pyroptosis.
• To explore the therapeutic potential of fumarate-based compounds in inflammatory diseases.

Main Methods:

• Cellular assays to assess pyroptosis inhibition.
• Biochemical analysis to identify protein modifications.
• In vivo studies in mouse models of inflammatory diseases.

Main Results:

• Fumarate, including dimethyl fumarate (DMF), was identified as an inhibitor of pyroptosis.
• Fumarate directly reacts with gasdermin D (GSDMD) at cysteine residues, forming S-(2-succinyl)-cysteine adducts.
• GSDMD succination inhibits its activation, processing, and pore formation, thereby preventing pyroptosis.
• DMF administration protected mice against lipopolysaccharide-induced shock and ameliorated symptoms in models of familial Mediterranean fever and experimental autoimmune encephalitis.

Conclusions:

• Gasdermin D (GSDMD) is a direct molecular target of fumarate.
• Fumarate-mediated GSDMD succination represents a novel mechanism to inhibit pyroptosis.
• Dimethyl fumarate (DMF) demonstrates therapeutic potential for inflammatory conditions, including multiple sclerosis, by targeting GSDMD.