Alanyl‐tRNA synthetase AARS1: A novel lactate sensor and lactyltransferase mediating p53 lactylation and tumorigenesis

作者：Qiqing Yang, Heyu Li, Long Zhang · 发表于：MedComm – Oncology · 年份：2024 · DOI：10.1002/mog2.83 · 被引用次数：1 · 研究领域：RNA modifications and cancer、RNA and protein synthesis mechanisms、RNA Research and Splicing

In a recent study published in Cell, Zong et al. discovered that alanyl-tRNA synthetase 1 (AARS1) senses the accumulated lactate and subsequently facilitates global lysine lactylation in tumor cells.1 Furthermore, they found that p53 is a crucial target protein of AARS1-mediated lactylation. Due to the structural similarity between lactate and l-alanine, AARS1 has the capability to directly bind to lactate and transfer it to the K120 and K139 residues of p53 under conditions involving ATP consumption. The lactylation of p53 impairs its DNA binding, liquid–liquid phase separation (LLPS), and transcriptional activation ability, ultimately promoting cancer progression. Additionally, the study revealed that β-alanine inhibits the binding of AARS1 to lactate, suggesting potential implications for cancer treatment. This study identified a novel lactate sensor and lactyltransferase, opening new avenues for furture research on lactylation. In 2019, Zhang et al. reported that lactate, which is a byproduct of glycolysis, can modify histones by lactylation.2 The Warburg effect explains how the tumor cells rely on glycolysis as the primary energy source, causing accumulation of high lactate levels. Besides, the acidic intratumoral environment causes protein lactylation, ultimately altering the functions of many proteins, promoting cancer progression. As our understanding of lactylation has increased, numerous “readers” and “erasers” of lactylation have been identified.3, 4 However, few “...