Aars1, short for alanyl-tRNA synthetase 1, is not only involved in the canonical function of charging alanine onto its cognate tRNA for protein synthesis but also has non-canonical roles. It has emerged as a key player in linking cellular metabolism to protein function through its role as a lactate sensor and lactyltransferase, which is associated with tumorigenesis-related pathways and may impact the Hippo pathway [1,2].

In cancer research, Aars1 has been shown to bind lactate, form lactate-AMP, and then lactylate proteins like p53 and YAP-TEAD complex. Lactylation of p53 by Aars1 hinders its liquid-liquid phase separation, DNA binding, and transcriptional activation, correlating with poor prognosis in wild-type p53-carrying cancer patients. In gastric cancer, Aars1 senses lactate, translocates to the nucleus to lactylate and activate the YAP-TEAD complex, and forms a positive-feedback loop with YAP-TEAD to promote cell proliferation [1,2]. In duodenal cancer, Aars1 is enhanced during progression, catalyzes the lysine-alanylation of PARP1, decreases cancer cell apoptosis, and promotes cell proliferation and tumorigenesis [5]. In addition, Aars1 has been associated with neurological and liver-related disorders. AARS1 deficiency has been linked to recurrent acute liver failure and Aars1-related white matter diseases with phenotypic variability [3,4].

In conclusion, Aars1 has diverse functions, playing a crucial role in tumorigenesis by coupling tumor cell metabolism to proteome alteration. It also contributes to the development of certain neurological and liver disorders. Studies on Aars1, especially through in vivo models, help us understand the molecular mechanisms underlying these diseases, providing potential targets for therapeutic intervention.

References:

1. Zong, Zhi, Xie, Feng, Wang, Shuai, Yang, Bing, Zhou, Fangfang. 2024. Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis. In Cell, 187, 2375-2392.e33. doi:10.1016/j.cell.2024.04.002. https://pubmed.ncbi.nlm.nih.gov/38653238/

2. Ju, Junyi, Zhang, Hui, Lin, Moubin, Jiao, Shi, Zhou, Zhaocai. 2024. The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer. In The Journal of clinical investigation, 134, . doi:10.1172/JCI174587. https://pubmed.ncbi.nlm.nih.gov/38512451/

3. Helman, Guy, Mendes, Marisa I, Nicita, Francesco, Vanderver, Adeline, Husain, Ralf A. 2021. Expanded phenotype of AARS1-related white matter disease. In Genetics in medicine : official journal of the American College of Medical Genetics, 23, 2352-2359. doi:10.1038/s41436-021-01286-8. https://pubmed.ncbi.nlm.nih.gov/34446925/

4. Marten, Lara M, Brinkert, Florian, Smith, Desirée E C, Hempel, Maja, Santer, René. 2020. Recurrent acute liver failure in alanyl-tRNA synthetase-1 (AARS1) deficiency. In Molecular genetics and metabolism reports, 25, 100681. doi:10.1016/j.ymgmr.2020.100681. https://pubmed.ncbi.nlm.nih.gov/33294374/

5. Li, Lingling, Jiang, Dongxian, Liu, Hui, Hou, Yingyong, Ding, Chen. 2023. Comprehensive proteogenomic characterization of early duodenal cancer reveals the carcinogenesis tracks of different subtypes. In Nature communications, 14, 1751. doi:10.1038/s41467-023-37221-5. https://pubmed.ncbi.nlm.nih.gov/36991000/