Leucyl‐tRNA synthetase is an amino acid sensor for the activation of Vps34 upstream of mTORC1 (1012.5)

Abstract

Amino acids availability regulates the mammalian target of rapamycin (mTOR) complex, mTORC1, a master regulator of cell growth. We previously reported that a pathway consisting of the class III PI‐3‐kinase Vps34 and the phospholipase PLD1 mediates amino acid activation of mTORC1, via PLD1 activation and translocation to the lysosome. The mechanism by which the Vps34‐PLD1 pathway senses amino acids is not known. In the current study, we identify leucyl‐tRNA synthetase (LRS) as the amino acid sensor for the activation of Vps34‐PLD1. LRS knockdown impaired amino acid‐induced Vps34 activation, cellular PI3P level increase, PLD1 activation, and PLD1 lysosomal translocation. Conversely, overexpression of LRS enhances activation of Vps34 and PLD by amino acids. Results with LRS mutants suggest that this function of LRS is dependent on its ability to bind leucine but independent of its tRNA charging activity. In addition, we find that LRS physically interacts with Vps34 through Vps15 and this interaction may be directly responsible for the activation of Vps34 in response to amino acids. Taken together, these observations strongly suggest that LRS mediates amino acid activation of Vps34‐PLD1 upstream of mTORC1. Our findings reveal a new regulator for Vps34 and fill a previous gap in the amino acid‐sensing signaling network.Grant Funding Source: NIH GM089771 and AR048914