The short-chain fatty acid metabolite acetyl-coenzyme A (acetyl-CoA) has emerged as a major signal transducer that can broadly affect cell fate and function, at least partly by influencing acetylation of key proteins. The mechanism by which acetyl-CoA regulates CD4~+ T-cell fate determination remains poorly understood. Herein, we report that acetate modulates glyceraldehyde-3-phosphate dehydrogenase (GAPDH) acetylation and CD4~+ T helper 1 (Th1) cell differentiation by altering acetyl-CoA levels. Our transcriptome profiling shows that acetate is a robust positive regulator of CD4~+ T-cell gene expression typical of glycolysis. We further show that acetate potentiates GAPDH activity, aerobic glycolysis, and Th1 polarization through regulation of GAPDH acetylation levels. This acetate-dependent GAPDH acetylation occurs in a dose- and time-dependent manner, while decreasing acetyl- CoA levels by fatty acid oxidation inhibition results in a decline in acetyl-GAPDH levels. Thus, acetate functions as a potent metabolic regulator in CD4~+ T-cells by promoting GAPDH acetylation and Th1 cell fate decision.
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