2. Academic Validation
  3. AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases

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

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. L_Zhang@zju.edu.cn.
  • 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. L_Zhang@zju.edu.cn.
  • 7 Cancer Center, Zhejiang University, Hangzhou, China. L_Zhang@zju.edu.cn.
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.

Figures
Products