Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway

Jung Min Han, Seung Jae Jeong, Min Chul Park, Gyuyoup Kim, Nam Hoon Kwon, Hoi Kyoung Kim, Sang Hoon Ha, Sung Ho Ryu, Sunghoon Kim

Research output: Contribution to journalArticlepeer-review

632 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)410-424
Number of pages15
Issue number2
Publication statusPublished - 2012 Apr 13

Bibliographical note

Funding Information:
We thank D.M. Sabatini, Y. Sancak, and J. Chung for advice. This work was supported by the Global Frontier Project grant NRF-M1AXA002-2011-0028417 and by R31-2008-000-10103-0 from the WCU project of the MEST. J.M.H., conception and design, collection and analysis of data, manuscript writing, final approval of manuscript; S.J.J., M.C.P., G.K., N.H.K., H.K.K., and S.H.H., collection and analysis of data; S.H.R, conception and design; S.K., conception and design, financial support, manuscript writing, and final approval of manuscript.

All Science Journal Classification (ASJC) codes

  • General Biochemistry,Genetics and Molecular Biology


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