title: SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1.
abstract: Cell growth and proliferation are tightly linked to nutrient availability. The mechanistic target of rapamycin complex 1 (mTORC1) integrates the presence of growth factors, energy levels, glucose and amino acids to modulate metabolic status and cellular responses. mTORC1 is activated at the surface of lysosomes by the RAG GTPases and the Ragulator complex through a not fully understood mechanism monitoring amino acid availability in the lysosomal lumen and involving the vacuolar H(+)-ATPase. Here we describe the uncharacterized human member 9 of the solute carrier family 38 (SLC38A9) as a lysosomal membrane-resident protein competent in amino acid transport. Extensive functional proteomic analysis established SLC38A9 as an integral part of the Ragulator-RAG GTPases machinery. Gain of SLC38A9 function rendered cells resistant to amino acid withdrawal, whereas loss of SLC38A9 expression impaired amino-acid-induced mTORC1 activation. Thus SLC38A9 is a physical and functional component of the amino acid sensing machinery that controls the activation of mTOR.
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Manuele
authors.initials: M
authors.lastname: Rebsamen
authors.affiliation: Department DiBEST (Biology, Ecology and Earth Sciences), University of Calabria, 87036 Arcavacata di Rende, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Pochini
authors.affiliation: Biocenter, Division of Cell Biology, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Taras
authors.initials: T
authors.lastname: Stasyk
authors.affiliation: Biocenter, Division of Cell Biology, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Mariana E G
authors.initials: ME
authors.lastname: de Araújo
authors.affiliation: Department DiBEST (Biology, Ecology and Earth Sciences), University of Calabria, 87036 Arcavacata di Rende, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Galluccio
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Kandasamy
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Berend
authors.initials: B
authors.lastname: Snijder
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Astrid
authors.initials: A
authors.lastname: Fauster
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Elena L
authors.initials: EL
authors.lastname: Rudashevskaya
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Manuela
authors.initials: M
authors.lastname: Bruckner
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Stefania
authors.initials: S
authors.lastname: Scorzoni
authors.affiliation: Biocenter, Division of Cell Biology, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Przemyslaw A
authors.initials: PA
authors.lastname: Filipek
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Kilian V M
authors.initials: KV
authors.lastname: Huber
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Johannes W
authors.initials: JW
authors.lastname: Bigenzahn
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Leonhard X
authors.initials: LX
authors.lastname: Heinz
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria.
authors.forename: Claudine
authors.initials: C
authors.lastname: Kraft
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.affiliation: Department DiBEST (Biology, Ecology and Earth Sciences), University of Calabria, 87036 Arcavacata di Rende, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Indiveri
authors.affiliation: Biocenter, Division of Cell Biology, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Lukas A
authors.initials: LA
authors.lastname: Huber
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
mesh_terms: D026905:Amino Acid Transport Systems / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D026905:Amino Acid Transport Systems; D000596:Amino Acids; D046912:Multiprotein Complexes; D009711:Nucleotides; C000594592:SLC38A9 protein, human; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C484342:RRAGA protein, human; D020559:Monomeric GTP-Binding Proteins