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

  • Nature. 2024 Sep 25. doi: 10.1038/s41586-024-07992-y.
Heyu Li  1 ,  Chao Liu  1 ,  Ran Li  2 ,  Lili Zhou  3 ,  Yu Ran  1 ,  Qiqing Yang  1 ,  Huizhe Huang  4 ,  Huasong Lu  1 ,  Hai Song  1 ,  Bing Yang  1 ,  Heng Ru  1 ,  Shixian Lin  1 ,  Long Zhang  5  6  7
Affiliations
  • 1. Life Sciences Institute and State Key Laboratory of Transvascular Implantation Devices of the Second Affiliated Hospital of the Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
  • 2. Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, Hangzhou City University School of Medicine, Hangzhou, China.
  • 3. Institutes of Biology and Medical Science, Soochow University, Suzhou, China.
  • 4. The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 5. Life Sciences Institute and State Key Laboratory of Transvascular Implantation Devices of the Second Affiliated Hospital of the Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China. [email protected].
  • 6. The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China. [email protected].
  • 7. Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
PMID: 39322678 DOI: 10.1038/s41586-024-07992-y
Abstract

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.

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