Abstract
Aminoacyl-tRNA synthetases are fundamental to the translation machinery with emerging roles in transcriptional regulation. Previous cellular studies have demonstrated tyrosyl-tRNA synthetase (YARS1 or TyrRS) as a stress response protein through its cytosol-nucleus translocation to maintain cellular homeostasis. Here, we established a mouse model with a disrupted TyrRS nuclear localization signal, revealing its systemic impact on metabolism. Nuclear TyrRS deficiency (YarsΔNLS) led to reduced lean mass, reflecting a mild developmental defect, and reduced fat mass, possibly due to increased energy expenditure. Consistently, YarsΔNLS mice exhibit improved insulin sensitivity and reduced insulin levels, yet maintain normoglycemia, indicative of enhanced insulin action. Notably, YarsΔNLS mice also develop progressive hearing loss. These findings underscore the crucial function of nuclear TyrRS in the maintenance of fat storage and hearing and suggest that aminoacyl-tRNA synthetases' regulatory roles can affect metabolic pathways and tissue-specific health. This work broadens our understanding of how protein synthesis interconnects metabolic regulation to ensure energy efficiency.