Report

Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity

See allHide authors and affiliations

Science  29 Mar 2018:
eaan4665
DOI: 10.1126/science.aan4665

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Abstract

Activated immune cells undergo a metabolic switch to aerobic glycolysis akin to the Warburg effect, presenting a potential therapeutic target in autoimmune disease. Dimethyl fumarate, 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, it covalently modifies cysteine residues in a process termed “succination.” Here, we show that dimethyl fumarate succinates and inactivates the catalytic cysteine of the glycolytic enzyme GAPDH both in vitro and in vivo. It thereby downregulates aerobic glycolysis in activated myeloid and lymphoid cells, which mediates its anti-inflammatory effects. Our findings provide mechanistic insight into immune modulation by dimethyl fumarate and represent a proof of concept that aerobic glycolysis is a therapeutic target in autoimmunity.

View Full Text