title: Leucyl-tRNA Synthetase Activates Vps34 in Amino Acid-Sensing mTORC1 Signaling.
abstract: Amino acid availability activates signaling by the mammalian target of rapamycin (mTOR) complex 1, mTORC1, a master regulator of cell growth. The class III PI-3-kinase Vps34 mediates amino acid signaling to mTORC1 by regulating lysosomal translocation and activation of the phospholipase PLD1. Here, we identify leucyl-tRNA synthetase (LRS) as a leucine sensor for the activation of Vps34-PLD1 upstream of mTORC1. LRS is necessary for amino acid-induced Vps34 activation, cellular PI(3)P level increase, PLD1 activation, and PLD1 lysosomal translocation. Leucine binding, but not tRNA charging activity of LRS, is required for this regulation. Moreover, LRS physically interacts with Vps34 in amino acid-stimulatable non-autophagic complexes. Finally, purified LRS protein activates Vps34 kinase in vitro in a leucine-dependent manner. Collectively, our findings provide compelling evidence for a direct role of LRS in amino acid activation of Vps34 via a non-canonical mechanism and fill a gap in the amino acid-sensing mTORC1 signaling network.
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, 601 South Goodwin Avenue B107, Urbana, IL 61801, USA; Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Republic of Korea. Electronic address: msyoon@gachon.ac.kr.
authors.forename: Mee-Sup
authors.initials: MS
authors.lastname: Yoon
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, 601 South Goodwin Avenue B107, Urbana, IL 61801, USA.
authors.forename: Kook
authors.initials: K
authors.lastname: Son
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, 601 South Goodwin Avenue B107, Urbana, IL 61801, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Arauz
authors.affiliation: Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul 120-749, Republic of Korea; College of Pharmacy, Yonsei University, Incheon 406-840, Republic of Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Han
authors.affiliation: Medicinal Bioconvergence Research Center, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, 601 South Goodwin Avenue B107, Urbana, IL 61801, USA. Electronic address: jiechen@illinois.edu.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D002460:Cell Line; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D006801:Humans; D007935:Leucine-tRNA Ligase / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000596:Amino Acids; D018129:Phosphatidylinositol Phosphates; C055525:phosphatidylinositol 3-phosphate; D058546:Class III Phosphatidylinositol 3-Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D007935:Leucine-tRNA Ligase