title: Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway.
abstract: 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.
authors.affiliation: Medicinal Bioconvergence Research Center, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Han
authors.forename: Seung Jae
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Min Chul
authors.initials: MC
authors.lastname: Park
authors.forename: Gyuyoup
authors.initials: G
authors.lastname: Kim
authors.forename: Nam Hoon
authors.initials: NH
authors.lastname: Kwon
authors.forename: Hoi Kyoung
authors.initials: HK
authors.lastname: Kim
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Ha
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Ryu
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy; D002460:Cell Line; D048429:Cell Size; D006801:Humans; D007930:Leucine / Q000378:metabolism*; D007935:Leucine-tRNA Ligase / Q000737:chemistry / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D014176:Protein Biosynthesis; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: D046912:Multiprotein Complexes; D011506:Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D007935:Leucine-tRNA Ligase; D007930:Leucine