苏州大学周芳芳团队发现，丙氨酰-tRNA合成酶AARS1是一种乳酸传感器和乳酸转移酶，可使p53乳酸化并促进肿瘤发生。相关论文于2024年4月22日在线发表在《细胞》杂志上。

研究人员发现AARS1可作为乳酸传感器介导肿瘤细胞中的全局赖氨酸乳化。AARS1与乳酸结合，催化乳酸-AMP的形成，然后将乳酸转移到赖氨酸受体残基上。蛋白质组学研究发现了大量AARS1靶点，包括p53，其中DNA结合域的赖氨酸120和赖氨酸139被乳酸化。研究人员生成并利用携带组成型赖氨酸残基的p53变体发现，AARS1对p53的乳酸化作用会阻碍其液相分离、DNA结合和转录激活。

AARS1的表达和p53的乳酸化与携带野生型p53的癌症患者预后不良有关。β-丙氨酸能破坏乳酸与AARS1的结合，减少p53的乳酸化，并减轻动物模型的肿瘤发生。研究人员认为，AARS1是通过将肿瘤细胞的新陈代谢，与蛋白质组的改变结合起来，来促进肿瘤发生的。

研究人员表示，赖氨酸乳酸化是一种将细胞代谢，与蛋白质功能联系起来的翻译后修饰。

附：英文原文

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

Author: Zhi Zong, Feng Xie, Shuai Wang, Xiaojin Wu, Zhenyu Zhang, Bing Yang, Fangfang Zhou

Issue&Volume: 2024-04-22

Abstract: Lysine lactylation is a post-translational modification that links cellular metabolismto protein function. Here, we find that AARS1 functions as a lactate sensor that mediatesglobal lysine lacylation in tumor cells. AARS1 binds to lactate and catalyzes theformation of lactate-AMP, followed by transfer of lactate to the lysince acceptorresidue. Proteomics studies reveal a large number of AARS1 targets, including p53where lysine 120 and lysine 139 in the DNA binding domain are lactylated. Generationand utilization of p53 variants carrying constitutively lactylated lysine residuesrevealed that AARS1 lactylation of p53 hinders its liquid-liquid phase separation,DNA binding, and transcriptional activation. AARS1 expression and p53 lacylation correlatewith poor prognosis among cancer patients carrying wild type p53. β-alanine disruptslactate binding to AARS1, reduces p53 lacylation, and mitigates tumorigenesis in animalmodels. We propose that AARS1 contributes to tumorigenesis by coupling tumor cellmetabolism to proteome alteration.

DOI: 10.1016/j.cell.2024.04.002

Source: https://www.cell.com/cell/abstract/S0092-8674(24)00397-0