N-terminomics upon Arginyl-tRNA synthetase knock down

Arginine is associated with inflammation, cancer, and amino acid signaling, in part through the mTORC1 pathway. In cell-based assays and in the mouse, we found that arginine regulates nuclear levels of arginyl-tRNA synthetase (ArgRS), and that arginine depletion and inflammation reduced nuclear ArgRS in vivo. In the nucleus, ArgRS interacted and co-localized with the spliceosomal Serine/Arginine Repetitive Matrix Protein 2 (SRRM2) that is crucial for the formation of nuclear speckle condensates. ArgRS mRNA silencing changed specific splice junction usages, and these inversely correlated with SRRM2-induced usage changes of the same junctions. The prominently affected genes encompassed components of the mTORC1 pathway and showed ArgRS, arginine, and SRRM2 are tied together as upstream regulators of nuclear condensate trafficking related to the physiological response to inflammatory injury. This study is the first to demonstrate a regulatory role for an aaRS in shaping nuclear condensate dynamics and RNA splicing.