Aminoacyl-Transfer RNA Synthetases Connecting Nutrient Status to Angiogenesis Through the Unfolded Protein Response

Aminoacyl-transfer RNA (tRNA) synthetases (AARSs) are well known for catalyzing the selective attachment of amino acids to their cognate tRNAs to ensure accurate protein translation. Evidence has accumulated in recent years that AARSs are involved in additional complex eukaryotic processes, including recruitment of immune cells and regulation of angiogenesis.1–4 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Castranova et al5 report an additional link between angiogenesis regulation and 2 specific AARSs, threonyl-tRNA synthetase (TARS) and isoleucyl-tRNA synthetase (IARS). In a genetic screen for altered vasculature, mutations in the tars and iars zebrafish genes were identified by classical genetic mapping and sequencing. The dysregulated vessel formation was associated with a premature stop codon in the tars gene and a point mutation in the iars gene. The phenotype caused by these mutations could be rescued by transgenes encoding the wild-type alleles. Further mechanistic studies showed that loss of TARS or IARS function leads to upregulation …