AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases

• 成果类型: Article
• 署名作者: Li, Heyu; Liu, Chao; Li, Ran; Zhou, Lili; Ran, Yu; Yang, Qiqing; Huang, Huizhe; Lu, Huasong; Song, Hai; Yang, Bing; Ru, Heng; Lin, Shixian; Zhang, Long
• 署名单位: Zhejiang University; Zhejiang University; Hangzhou City University; Soochow University - China; Chongqing Medical University; Nanchang University; Zhejiang University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4121
• DOI: 10.1038/s41586-024-07992-y
• 发表日期: 2024-10-31
• 页码: 1229-1237
• 关键词: cyclic gmp-amp; dna sensor; 2nd-messenger; dinucleotide; metabolism; synthase; cells

摘要

l-lactate modifies proteins through lactylation1, but how this process occurs is unclear. Here we identify the alanyl-tRNA synthetases AARS1 and AARS2 (AARS1/2) as intracellular l-lactate sensors required for l-lactate to stimulate the lysine lactylome in cells. AARS1/2 and the evolutionarily conserved Escherichia coli orthologue AlaRS bind to l-lactate with micromolar affinity and they directly catalyse l-lactate for ATP-dependent lactylation on the lysine acceptor end. In response to l-lactate, AARS2 associates with cyclic GMP-AMP synthase (cGAS) and mediates its lactylation and inactivation in cells and in mice. By establishing a genetic code expansion orthogonal system for lactyl-lysine incorporation, we demonstrate that the presence of a lactyl moiety at a specific cGAS amino-terminal site abolishes cGAS liquid-like phase separation and DNA sensing in vitro and in vivo. A lactyl mimetic knock-in inhibits cGAS, whereas a lactyl-resistant knock-in protects mice against innate immune evasion induced through high levels of l-lactate. MCT1 blockade inhibits cGAS lactylation in stressed mice and restores innate immune surveillance, which in turn antagonizes viral replication. Thus, AARS1/2 are conserved intracellular l-lactate sensors and have an essential role as lactyltransferases. Moreover, a chemical reaction process of lactylation targets and inactivates cGAS.