The lysine acetyltransferase KAT6A epigenetically facilitates glucose metabolic programming and CD4 T cell responses in autoimmunity

Epigenetic programs are pivotal regulators of effector CD4 T cells and determine the fate of many autoimmune disorders. Here, we show that the acetyltransferase KAT6A acts as a novel regulator of glucose metabolism that is required for the proliferation and effector functions of CD4 T cells in autoimmunity. Clinical analysis shows that KAT6A in CD4 T cells is linked to the progression of autoimmune Sjogrens syndrome. Conditional knockout of KAT6A inhibits the proliferation and Th1Th17 effector functions of CD4 T cells both in vitro and that KAT6AcKO CD4 T cells are less susceptible to induce adjuvantimmunized experimental autoimmune encephalomyelitis, autoimmune colitis and experimental SS. Combination of metabolomic, epigenetic and transcriptomic analyses show that KAT6A maintains abundant acetylation of H3K9ac and H3K27ac sites of several glycolytic genes, which in turn disrupts the transcriptional activation of MYC and HIF1a, and potentiates the metabolic programming of glycolysis through its enzymatic amino acid points. Treatment with KAT6A smallmolecule inhibitors in various autoimmune mice models shows high therapeutic value for targeting KAT6A to the treatment of autoimmune disorders. Our study reveals a critical role for KAT6A in autoimmunity via the epigenetic modification of glucose metabolic reprogramming and the effector response of CD4 T cells.