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The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer
Junyi Ju, … , Shi Jiao, Zhaocai Zhou
Junyi Ju, … , Shi Jiao, Zhaocai Zhou
Published March 21, 2024
Citation Information: J Clin Invest. 2024;134(10):e174587. https://doi.org/10.1172/JCI174587.
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Research Article Metabolism

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

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Abstract

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.

Authors

Junyi Ju, Hui Zhang, Moubin Lin, Zifeng Yan, Liwei An, Zhifa Cao, Dandan Geng, Jingwu Yue, Yang Tang, Luyang Tian, Fan Chen, Yi Han, Wenjia Wang, Shimin Zhao, Shi Jiao, Zhaocai Zhou

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Figure 2

AARS1 directly interacts with and lactylates YAP-TEAD.

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AARS1 directly interacts with and lactylates YAP-TEAD.
(A) Lysine lactyl...
(A) Lysine lactylome in lactate-treated HGC27 cells. A total of 1,182 lactylated proteins and 2,789 lactylated sites with q value (–log10) greater than 10 were identified. Histone sites modified through lactylation are shown in gray. Lactylation on Hippo pathway–associated components are shown in red. (B) KEGG pathway analysis of lactylated proteins identified using lactylation proteomics in HGC27 cells cultured in glucose-free medium supplemented with 25 mM lactate. (C) Mass spectra of lactylated sites of YAP (K90) and TEAD1 (K108). (D) Immunoblotting showing the lactylation of endogenous YAP and TEAD1 proteins using pan-Klac antibody. (E) Lactylation levels of exogenous YAP and TEAD1 in cells transfected with the indicated plasmids. (F and G) Lactylation levels of endogenous YAP (F) and TEAD1 (G) in lactate-treated HGC27 cells. Glc, glucose; Lac, lactate. (H) Coimmunoprecipitation analysis of the endogenous interaction between YAP (left) or TEAD1 (right) and AARS1 in lactate-treated HGC27 cells. (I) Pull-down assay showing the direct interaction between AARS1 and YAP-TEAD1. Top: MBP pull-down assay to detect interaction between AARS1 and MBP-YAP (1–291). Bottom: GST pull-down assay to detect interaction between GST-AARS1 and His-sumo-TEAD1 (HS-TEAD1). Asterisks represent the indicated proteins. (J) Mass spectrometry to determine the lactylation of the synthetic YAP K90 and TEAD1 K108 peptides catalyzed by AARS1 and its catalytic-dead mutant 5M in vitro. (K) Immunoblotting with pan-Klac antibody to detect AARS1-induced lactylation of TEAD1 in vitro. CBB staining showing the purified AARS1 and TEAD1 used in in vitro lactylation assay. Asterisks represent the AARS1 and TEAD1 proteins. The final concentrations of PPi in the reaction mixture were 2 mM (+) and 10 mM (++), respectively. (L) Lactylation levels of YAP (left) and TEAD1 (right) in cells overexpressing AARS1 or its 5M mutant. (M) Lactylation levels of YAP (left) and TEAD1 (right) in AARS1-knockdown HEK293FT cells.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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