Human aminoacyl-tRNA synthetases as integrators of translation and cell signalling networks

Aminoacyl-tRNA synthetases (ARSs) are best known for their central role in translation, where they attach specific amino acids to their matching tRNAs to ensure accurate protein synthesis. However, in humans, these enzymes have evolved far beyond this textbook function. Emerging research reveals that ARSs have versatile roles in cells, acting as sensors, signalling hubs and regulators of cellular and systemic homeostasis. The structural adaptability of ARSs enables them to connect metabolic cues with gene expression, protein networks and stress responses. Disruptions in ARS functions are increasingly linked to a wide range of diseases, from cancer to neurodegeneration. In this Review, we examine how ARSs operate at the intersection of translation and signalling networks: we discuss their catalytic regulation functions, structural diversification, non-canonical functions such as in transcription and translation regulation, protein degradation and signal transduction and their disease relevance. By bringing these insights together, we offer a unified view of ARSs as multifaceted proteins and open new avenues for discoveries in molecular biology, pathophysiology and drug design.