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Lysine acetyltransferase 6A maintains CD4+ Tcell response via epigenetic reprogramming of glucose metabolism in autoimmunity

Fu, JY;Huang, SJ;Wang, BL;Yin, JH;Chen, CY;Xu, JB;Chen, YL;Xu, S;Dong, T;Zhou, HN;Ma, XY;Pu, YP;Li, H;Yang, XJ;Xie, LS;Wang, ZJ;Luo, Q;Shao, YX;Ye, L;Zong, ZR;Wei, XD;Xiao, WW;Niu, ST;Liu, YM;Xu, HP;Yu, CQ;Duan, SZ;Zheng, LY;

Augmented CD4+ T cell response in autoimmunity is characterized by extensive metabolic reprogramming. However, the epigenetic molecule that drives the metabolic adaptation of CD4+ T cells remains largely unknown. Here, we show that lysine acetyltransferase 6A (KAT6A), an epigenetic modulator that is clinically associated with autoimmunity, orchestrates the metabolic reprogramming of glucose in CD4+ T cells. KAT6A is required for the proliferation and differentiation of proinflammatory CD4+ T cell subsets in vitro, and mice with KAT6A-deficient CD4+ T cells are less susceptible to experimental autoimmune encephalomyelitis and colitis. Mechanistically, KAT6A orchestrates the abundance of histone acetylation at the chromatin where several glycolytic genes are located, thus affecting glucose metabolic reprogramming and subsequent CD4+ T cell responses. Treatment with KAT6A small-molecule inhibitors in mouse models shows high therapeutic value for targeting KAT6A in autoimmunity. Our study provides novel insights into the epigenetic programming of immunometabolism and suggests potential therapeutic targets for patients with autoimmunity.