Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalScience
DOIs
StateAccepted/In press - Mar 29 2018

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Glycolysis
Immunity
Cysteine
Fumarates
Citric Acid Cycle
Myeloid Cells
Autoimmunity
Psoriasis
Autoimmune Diseases
Multiple Sclerosis
Anti-Inflammatory Agents
Therapeutics
Down-Regulation
Lymphocytes
Enzymes
Pharmaceutical Preparations
Dimethyl Fumarate

ASJC Scopus subject areas

  • General

Cite this

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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.",
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AU - Kornberg, Michael

AU - Bhargava, Pavan

AU - Kim, Paul

AU - Putluri, Vasanta

AU - Snowman, Adele M

AU - Putluri, Nagireddy

AU - Calabresi, Peter

AU - Snyder, Solomon H

PY - 2018/3/29

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