Accession PRJCA024613
Title AARS1/2 senses L-lactate for cGAS regulation as lysine lactyltransferase
Relevance Medical
Data types Transcriptome or Gene expression
Organisms Homo sapiens
Bacteria
Description L-Lactate has been recently reported to modify proteins via lactylation but how this occurs is not clear. Here we identifishowed AARS1 and AARS2 (AARS1/2) as intracellular L-lactate sensor, required for L-lactate to stimulate lysine lactylome in cells. AARS1/2 and the evolutionarily conserved E. coli ortholog AlaRS bind to L-lactate with a dissociation constant of 7.5-20 micromolar affinity and they directly catalyze L-lactate for an ATP-dependent lactylation on lysine acceptor end. In response to L-lactate, AARS2 associates with cGAS and mediates its lactylation and inactivation in cells and mice. By establishing a genetic code expansion orthogonal system for lactyl-lysine incorporation, we demonstrated the presence of a lactyl moiety at specific cGAS N-terminal site abolishes cGAS LLPS and the DNA-sensing both in vitro and in vivo. Whereas the lactyl-mimetic knock-in inhibits cGAS, lactyl-resistant knock-in protects mice against the innate-immune evasion induced by high levels of L-lactate.
Sample scope Multiisolate
Release date 2024-04-23
Publication
PubMed ID Article title Journal name DOI Year
39322678 AARS1 and AARS2 sense l-lactate to regulate cGAS as global lysine lactyltransferases Nature 10.1038/s41586-024-07992-y 2024
Grants
Agency program Grant ID Grant title
Ministry of Science and Technology of the People's Republic of China (MOST) 2021YFA1101000
National Natural Science Foundation of China (NSFC) U20A20393
National Natural Science Foundation of China (NSFC) U20A201376
Submitter Zhang Long (l_zhang@zju.edu.cn)
Organization Life Sciences Institute, Zhejiang University
Submission date 2024-03-23

Project Data

Resource name Description
BioSample (11)  show -