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 |