Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis

Zhi Zong; Feng Xie; Shuai Wang; Xiaojin Wu; Zhenyu Zhang; Bing Yang; Fangfang Zhou

doi:10.1016/j.cell.2024.04.002

Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis

Cell. 2024 Apr 17:S0092-8674(24)00397-0. doi: 10.1016/j.cell.2024.04.002. Online ahead of print.

Authors

Zhi Zong¹, Feng Xie², Shuai Wang², Xiaojin Wu¹, Zhenyu Zhang³, Bing Yang⁴, Fangfang Zhou⁵

Affiliations

¹ The First Affiliated Hospital, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China.
² The First Affiliated Hospital, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China; MOE Key Laboratory of Geriatric Disease and Immunology, Soochow University, Suzhou, Jiangsu, China; Jiangsu key laboratory of Infection and Immunity, Soochow University, Suzhou, Jiangsu, China.
³ Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
⁴ Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
⁵ The First Affiliated Hospital, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China; MOE Key Laboratory of Geriatric Disease and Immunology, Soochow University, Suzhou, Jiangsu, China; Jiangsu key laboratory of Infection and Immunity, Soochow University, Suzhou, Jiangsu, China. Electronic address: zhoufangfang@suda.edu.cn.

PMID: 38653238
DOI: 10.1016/j.cell.2024.04.002

Abstract

Lysine lactylation is a post-translational modification that links cellular metabolism to protein function. Here, we find that AARS1 functions as a lactate sensor that mediates global lysine lacylation in tumor cells. AARS1 binds to lactate and catalyzes the formation of lactate-AMP, followed by transfer of lactate to the lysince acceptor residue. Proteomics studies reveal a large number of AARS1 targets, including p53 where lysine 120 and lysine 139 in the DNA binding domain are lactylated. Generation and utilization of p53 variants carrying constitutively lactylated lysine residues revealed that AARS1 lactylation of p53 hinders its liquid-liquid phase separation, DNA binding, and transcriptional activation. AARS1 expression and p53 lacylation correlate with poor prognosis among cancer patients carrying wild type p53. β-alanine disrupts lactate binding to AARS1, reduces p53 lacylation, and mitigates tumorigenesis in animal models. We propose that AARS1 contributes to tumorigenesis by coupling tumor cell metabolism to proteome alteration.

Keywords: AARS1; LLPS; alanyl-tRNA synthetase 1; lactate; lactylation; lactyltransferase; liquid-liquid phase separation; p53; tumor progression; β-alanine.