Cell Metab. 2024 Nov 12. pii: S1550-4131(24)00411-X. [Epub ahead of print]
Rongxuan Zhu,
Xianglai Ye,
Xiaotong Lu,
Liwei Xiao,
Ming Yuan,
Hong Zhao,
Dong Guo,
Ying Meng,
Hongkuan Han,
Shudi Luo,
Qingang Wu,
Xiaoming Jiang,
Jun Xu,
Zhonghui Tang,
Yizhi Jane Tao,
Zhimin Lu.
Lactyl-coenzyme A (CoA)-dependent histone lysine lactylation impacts gene expression and plays fundamental roles in biological processes. However, mammalian lactyl-CoA synthetases and their regulation of histone lactylation have not yet been identified. Here, we demonstrate that epidermal growth factor receptor (EGFR) activation induces extracellular signal-regulated kinase (ERK)-mediated S267 phosphorylation of acetyl-CoA synthetase 2 (ACSS2) and its subsequent nuclear translocation and complex formation with lysine acetyltransferase 2A (KAT2A). Importantly, ACSS2 functions as a bona fide lactyl-CoA synthetase and converts lactate to lactyl-CoA, which binds to KAT2A as demonstrated by a co-crystal structure analysis. Consequently, KAT2A acts as a lactyltransferase to lactylate histone H3, leading to the expression of Wnt/β-catenin, NF-κB, and PD-L1 and brain tumor growth and immune evasion. A combination treatment with an ACSS2-KAT2A interaction-blocking peptide and an anti-PD-1 antibody induces an additive tumor-inhibitory effect. These findings uncover ACSS2 and KAT2A as hitherto unidentified lactyl-CoA synthetase and lactyltransferase, respectively, and the significance of the ACSS2-KAT2A coupling in gene expression and tumor development.
Keywords: ACSS2; KAT2A; PD-L1; histone lactylation; lactate