Jung Min Han,1 Seung Jae Jeong,1 Min Chul Park,1 Gyuyoup Kim,1 Nam Hoon Kwon,1 Hoi Kyoung Kim,1 Sang Hoon Ha,2 Sung Ho Ryu,2 and Sunghoon Kim1,3,*
1Medicinal Bioconvergence Research Center, Seoul National University, Seoul 151-742, Republic of Korea
2Division of Molecular and Life Sciences, POSTECH, Pohang 790-784, Republic of Korea
3WCU Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology,Seoul National University, Suwon 443-270, Republic of Korea
*Correspondence: Sunghoon Kim
Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase, which regulates protein translation, cell size, and autophagy. However, the amino acid sensor that directly couples intracellular amino acid-mediated signaling to mTORC1 is unknown. Here we show that leucyl-tRNA synthetase (LRS) plays a critical role in amino acid-induced mTORC1 activation by sensing intracellular leucine concentration and initiating molecular events leading to mTORC1 activation. Mutation of LRS amino acid residues important for leucine binding renders the mTORC1 pathway insensitive to intracellular levels of amino acids. We show that LRS directly binds to Rag GTPase, the mediator of amino acid signaling to mTORC1, in an amino acid-dependent manner and functions as a GTPase-activating protein (GAP) for Rag GTPase to activate mTORC1. This work demonstrates that LRS is a key mediator for amino acid signaling to mTORC1.