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

Heyu Li, Chao Liu, Ran Li, Lili Zhou, Yu Ran, Qiqing Yang, Huizhe Huang, Huasong Lu, Hai Song, Bing Yang, Heng Ru, Shixian Lin and Long Zhang ()
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Heyu Li: Zhejiang University
Chao Liu: Zhejiang University
Ran Li: Hangzhou City University School of Medicine
Lili Zhou: Soochow University
Yu Ran: Zhejiang University
Qiqing Yang: Zhejiang University
Huizhe Huang: The Second Affiliated Hospital of Chongqing Medical University
Huasong Lu: Zhejiang University
Hai Song: Zhejiang University
Bing Yang: Zhejiang University
Heng Ru: Zhejiang University
Shixian Lin: Zhejiang University
Long Zhang: Zhejiang University

Nature, 2024, vol. 634, issue 8036, 1229-1237

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07992-y

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