Journal Article

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

Liu, Chao, Yang, Bing, Li, Heyu, Ran, Yu, Li, Ran, Yang, Qiqing, Lin, Shixian, Zhou, Lili, Zhang, Long, Song, Hai, Lu, Huasong, Ru, Heng, Huang, Huizhe

2024

Overview

l -lactate modifies proteins through lactylation 1 , 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. The tRNA synthases AARS1 and AARS2 are identified as evolutionarily conserved sensors of intracellular l -lactate to mediate the global lysine lactylome.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/262 / 631/45/173 / 631/80/458 / 692/420/254 / 692/699/249 / Adenosine Triphosphate - metabolism / Alanine-tRNA Ligase - metabolism / Animals / Biocatalysis / Chemical reactions / Chemical sensors / DNA - immunology / E coli / Escherichia coli - enzymology / Female / Gene Knock-In Techniques / Genetic Code / Herpes viruses / Humanities and Social Sciences / Humans / Immune Evasion / Immunity, Innate / Immunosurveillance / Inactivation / Intracellular / Lactic acid / Lactic Acid - chemistry / Lactic Acid - metabolism / Lysine / Lysine - chemistry / Lysine - metabolism / Male / Mice / multidisciplinary / Nucleotidyltransferases - antagonists & inhibitors / Nucleotidyltransferases - chemistry / Nucleotidyltransferases - metabolism / Phase Separation / Proteins / Science / Science (multidisciplinary) / Sensors / Transfer RNA / tRNA / Virus Replication