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

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

doi:10.1016/j.cmet.2024.10.015

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

Cell Metab. 2024 Nov 12:S1550-4131(24)00411-X. doi: 10.1016/j.cmet.2024.10.015. Online ahead of print.

Authors

Rongxuan Zhu¹, Xianglai Ye¹, Xiaotong Lu², Liwei Xiao¹, Ming Yuan³, Hong Zhao¹, Dong Guo¹, Ying Meng¹, Hongkuan Han¹, Shudi Luo¹, Qingang Wu¹, Xiaoming Jiang¹, Jun Xu⁴, Zhonghui Tang³, Yizhi Jane Tao⁵, Zhimin Lu⁶

Affiliations

¹ Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China.
² Department of BioSciences, Rice University, Houston, TX 77005, USA.
³ Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
⁴ Genetics and Metabolism Department, The Children's Hospital, School of Medicine, Zhejiang University, National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310052, China.
⁵ Department of BioSciences, Rice University, Houston, TX 77005, USA. Electronic address: ytao@rice.edu.
⁶ Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310029, China. Electronic address: zhiminlu@zju.edu.cn.

PMID: 39561764
DOI: 10.1016/j.cmet.2024.10.015

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.

Keywords: ACSS2; KAT2A; PD-L1; histone lactylation; lactate.