Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity

Science. 2018 Apr 27;360(6387):449-453. doi: 10.1126/science.aan4665. Epub 2018 Mar 29.

Abstract

Activated immune cells undergo a metabolic switch to aerobic glycolysis akin to the Warburg effect, thereby presenting a potential therapeutic target in autoimmune disease. Dimethyl fumarate (DMF), a derivative of the Krebs cycle intermediate fumarate, is an immunomodulatory drug used to treat multiple sclerosis and psoriasis. Although its therapeutic mechanism remains uncertain, DMF covalently modifies cysteine residues in a process termed succination. We found that DMF succinates and inactivates the catalytic cysteine of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in mice and humans, both in vitro and in vivo. It thereby down-regulates aerobic glycolysis in activated myeloid and lymphoid cells, which mediates its anti-inflammatory effects. Our results provide mechanistic insight into immune modulation by DMF and represent a proof of concept that aerobic glycolysis is a therapeutic target in autoimmunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases / drug therapy
  • Autoimmune Diseases / enzymology
  • Autoimmunity / drug effects*
  • Citric Acid Cycle
  • Cysteine / metabolism
  • Dimethyl Fumarate / pharmacology*
  • Dimethyl Fumarate / therapeutic use
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism*
  • Glycolysis / drug effects*
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • Immunosuppressive Agents / therapeutic use
  • Lymphocytes / drug effects
  • Lymphocytes / enzymology
  • Lymphocytes / immunology
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells / drug effects
  • Myeloid Cells / enzymology
  • Myeloid Cells / immunology
  • Succinates / chemistry

Substances

  • Immunosuppressive Agents
  • Succinates
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
  • Dimethyl Fumarate
  • Cysteine