4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects

Shan-Ting Liao; Chao Han; Ding-Qiao Xu; Xiao-Wei Fu; Jun-Song Wang; Ling-Yi Kong

doi:10.1038/s41467-019-13078-5

4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects

Nat Commun. 2019 Nov 8;10(1):5091. doi: 10.1038/s41467-019-13078-5.

Authors

Shan-Ting Liao¹, Chao Han¹, Ding-Qiao Xu¹, Xiao-Wei Fu¹, Jun-Song Wang², Ling-Yi Kong³

Affiliations

¹ Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, 210009, Nanjing, China.
² Center for Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiao Ling Wei, 210014, Nanjing, China. [email protected].
³ Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, 210009, Nanjing, China. [email protected].

Abstract

Activated macrophages switch from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect, presenting a potential therapeutic target in inflammatory disease. The endogenous metabolite itaconate has been reported to regulate macrophage function, but its precise mechanism is not clear. Here, we show that 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) directly alkylates cysteine residue 22 on the glycolytic enzyme GAPDH and decreases its enzyme activity. Glycolytic flux analysis by U¹³C glucose tracing provides evidence that 4-OI blocks glycolytic flux at GAPDH. 4-OI thereby downregulates aerobic glycolysis in activated macrophages, which is required for its anti-inflammatory effects. The anti-inflammatory effects of 4-OI are replicated by heptelidic acid, 2-DG and reversed by increasing wild-type (but not C22A mutant) GAPDH expression. 4-OI protects against lipopolysaccharide-induced lethality in vivo and inhibits cytokine release. These findings show that 4-OI has anti-inflammatory effects by targeting GAPDH to decrease aerobic glycolysis in macrophages.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkylation
Animals
Antimetabolites / pharmacology
Cysteine / drug effects
Cysteine / genetics
Cysteine / metabolism
Deoxyglucose / pharmacology
Down-Regulation
Endotoxemia / immunology
Glucose / metabolism
Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / antagonists & inhibitors
Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / drug effects*
Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism
Glycolysis / drug effects*
Inflammation / immunology
Interleukin-1beta / drug effects
Interleukin-1beta / immunology
Lipopolysaccharides / pharmacology
Macrophage Activation / immunology
Macrophages / drug effects*
Macrophages / immunology
Macrophages / metabolism
Mice
Nitric Oxide Synthase Type II / drug effects
Nitric Oxide Synthase Type II / immunology
Oxidative Phosphorylation / drug effects
RAW 264.7 Cells
Sesquiterpenes / pharmacology
Succinates / pharmacology*

Substances

Antimetabolites
IL1B protein, mouse
Interleukin-1beta
Lipopolysaccharides
Sesquiterpenes
Succinates
heptelidic acid
Deoxyglucose
Nitric Oxide Synthase Type II
Nos2 protein, mouse
Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
Glucose
Cysteine
itaconic acid