2024年11月18日，浙江大学吕志明等研究人员合作在《细胞—代谢》杂志发表论文。该研究表面，ACSS2作为乳酰-CoA合成酶作用并将KAT2A耦合为乳酰转移酶，来促进组蛋白乳酸化与肿瘤免疫逃逸。

研究人员展示了表皮生长因子受体（EGFR）激活通过外源信号调节激酶（ERK）介导的S267磷酸化作用于乙酰-辅酶A（CoA）合成酶2（ACSS2），并导致其随后核转位和与赖氨酸乙酰转移酶2A（KAT2A）形成复合物。

重要的是，ACSS2作为一种真正的乳酰-CoA合成酶，将乳酸转化为乳酰-CoA，并与KAT2A结合，这一过程通过共晶结构分析得到验证。因此，KAT2A作为乳酰转移酶，将乳酰基转移到组蛋白H3上，进而激活Wnt/β-连环蛋白、NF-κB和PD-L1的表达，促进脑肿瘤生长和免疫逃逸。

使用ACSS2-KAT2A相互作用阻断肽和抗PD-1抗体的联合治疗，诱导了附加的肿瘤抑制效应。

这些发现揭示了ACSS2和KAT2A分别作为迄今未识别的乳酰-CoA合成酶和乳酰转移酶，并强调了ACSS2-KAT2A耦合在基因表达和肿瘤发展中的重要性。

研究人员表示，乳酰CoA依赖的组蛋白赖氨酸乳酰化影响基因表达，并在生物过程中发挥基础作用。然而，哺乳动物乳酰-CoA合成酶及其对组蛋白乳酰化的调控尚未被确定。

附：英文原文

Title: ACSS2 acts as a lactyl-CoA synthetase and couples KAT2A to function as a lactyltransferase for histone lactylation and tumor immune evasion

Author: 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

Issue&Volume: 2024-11-18

Abstract: 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.

DOI: 10.1016/j.cmet.2024.10.015

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00411-X