The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer

J Clin Invest. 2024 Mar 21;134(10):e174587. doi: 10.1172/JCI174587.


Lactylation has been recently identified as a new type of posttranslational modification occurring widely on lysine residues of both histone and nonhistone proteins. The acetyltransferase p300 is thought to mediate protein lactylation, yet the cellular concentration of the proposed lactyl-donor, lactyl-coenzyme A, is about 1,000 times lower than that of acetyl-CoA, raising the question of whether p300 is a genuine lactyltransferase. Here, we report that alanyl-tRNA synthetase 1 (AARS1) moonlights as a bona fide lactyltransferase that directly uses lactate and ATP to catalyze protein lactylation. Among the candidate substrates, we focused on the Hippo pathway, which has a well-established role in tumorigenesis. Specifically, AARS1 was found to sense intracellular lactate and translocate into the nucleus to lactylate and activate the YAP-TEAD complex; and AARS1 itself was identified as a Hippo target gene that forms a positive-feedback loop with YAP-TEAD to promote gastric cancer (GC) cell proliferation. Consistently, the expression of AARS1 was found to be upregulated in GC, and elevated AARS1 expression was found to be associated with poor prognosis for patients with GC. Collectively, this work found AARS1 with lactyltransferase activity in vitro and in vivo and revealed how the metabolite lactate is translated into a signal of cell proliferation.

Keywords: Cancer; Metabolism.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Alanine-tRNA Ligase* / genetics
  • Alanine-tRNA Ligase* / metabolism
  • Amino Acyl-tRNA Synthetases / genetics
  • Amino Acyl-tRNA Synthetases / metabolism
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lactic Acid / metabolism
  • Mice
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Signal Transduction*
  • Stomach Neoplasms* / enzymology
  • Stomach Neoplasms* / genetics
  • Stomach Neoplasms* / pathology
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • YAP-Signaling Proteins* / genetics
  • YAP-Signaling Proteins* / metabolism


  • Adaptor Proteins, Signal Transducing
  • Amino Acyl-tRNA Synthetases
  • Lactic Acid
  • Neoplasm Proteins
  • Transcription Factors
  • YAP-Signaling Proteins
  • AARS1 protein, human
  • Alanine-tRNA Ligase