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.

赖氨酸乳酰化是一种翻译后修饰，将细胞代谢与蛋白质功能联系起来。在这里，我们发现 AARS1 作为乳酸传感器发挥作用，介导肿瘤细胞中的整体赖氨酸酰化。 AARS1 与乳酸结合并催化乳酸-AMP 的形成，然后将乳酸转移至裂解受体残基。蛋白质组学研究揭示了大量 AARS1 靶标，包括 p53，其中 DNA 结合域中的赖氨酸 120 和赖氨酸 139 被乳酰化。携带组成型乳酰化赖氨酸残基的 p53 变体的产生和利用表明，p53 的 AARS1 乳酰化阻碍了其液-液相分离、DNA 结合和转录激活。在携带野生型 p53 的癌症患者中，AARS1 表达和 p53 酰化与不良预后相关。 β-丙氨酸破坏乳酸与 AARS1 的结合，减少 p53 酰化，并减轻动物模型中的肿瘤发生。我们认为 AARS1 通过将肿瘤细胞代谢与蛋白质组改变耦合来促进肿瘤发生。