Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity

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.

Source: ScienceNOW - April 26, 2018 Category: Science Authors: Kornberg, M. D., Bhargava, P., Kim, P. M., Putluri, V., Snowman, A. M., Putluri, N., Calabresi, P. A., Snyder, S. H. Tags: Immunology, Medicine, Diseases reports Source Type: news