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Aminoacyl-tRNA synthetases (ARSs) are a family of essential "housekeeping" enzymes ubiquitous in the three major domains of life. ARSs uniquely connect the essential minimal units of both major oligomer classes-the 3-nucleotide codons of oligonucleotides and the amino acids of proteins. They catalyze the esterification of amino acids to the 3'-end of cognate transfer RNAs (tRNAs) bearing the correct anticodon triplet to ensure accurate transfer of information from mRNA to protein according to the genetic code. As an essential translation factor responsible for the first biochemical reaction in protein biosynthesis, ARSs control protein production by catalyzing aminoacylation, and by editing of mischarged aminoacyl-tRNAs to maintain translational fidelity. In addition to their primary enzymatic activities, many ARSs have noncanonical functions unrelated to their catalytic activity in protein synthesis. Among the ARSs with "moonlighting" activities, several, including GluProRS (or EPRS), LeuRS, LysRS, SerRS, TyrRS, and TrpRS, exhibit cell signaling-related activities that sense environmental signals, regulate gene expression, and modulate cellular functions. ARS signaling functions generally depend on catalytically-inactive, appended domains not present in ancient enzyme forms, and are activated by stimulus-dependent post-translational modification. Activation often results in cellular re-localization and gain of new interacting partners. The newly formed ARS-bearing complexes conduct a host of signal transduction functions, including immune response, mTORC1 pathway signaling, and fibrogenic and angiogenic signaling, among others. Because noncanonical functions of ARSs in signal transduction are uncoupled from canonical aminoacylation functions, function-specific inhibitors can be developed, thus providing promising opportunities and therapeutic targets for treatment of human disease. © 2020 Elsevier Inc. All rights reserved.


Peng Yao, Paul L Fox. Aminoacyl-tRNA synthetases in cell signaling. The Enzymes. 2020;48:243-275

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PMID: 33837706

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