title: Requirement for lysosomal localization of mTOR for its activation differs between leucine and other amino acids.
abstract: The mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and metabolism. It controls many cell functions by integrating nutrient availability and growth factor signals. Amino acids, and in particular leucine, are among the main positive regulators of mTORC1 signaling. The current model for the regulation of mTORC1 by amino acids involves the movement of mTOR to the lysosome mediated by the Rag-GTPases. Here, we have examined the control of mTORC1 signaling and mTOR localization by amino acids and leucine in serum-fed cells, because both serum growth factors (or, e.g., insulin) and amino acids are required for full activation of mTORC1 signaling. We demonstrate that mTORC1 activity does not closely correlate with the lysosomal localization of mTOR. In particular, leucine controls mTORC1 activity without any detectable modification of the lysosomal localization of mTOR, indicating that the signal(s) exerted by leucine is likely distinct from those exerted by other amino acids. In addition, knock-down of the Rag-GTPases attenuated the inhibitory effect of amino acid- or leucine-starvation on the phosphorylation of mTORC1 targets. Furthermore, data from cells where Rag expression has been knocked down revealed that leucine can promote mTORC1 signaling independently of the lysosomal localization of mTOR. Our data complement existing models for the regulation of mTORC1 by amino acids and provide new insights into this important topic.
authors.affiliation: INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France; Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France. Electronic address: julien.averous@clermont.inra.fr.
authors.forename: Julien
authors.initials: J
authors.lastname: Averous
authors.affiliation: INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France; Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lambert-Langlais
authors.affiliation: INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France; Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Carraro
authors.affiliation: INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France; Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
authors.forename: Ophélie
authors.initials: O
authors.lastname: Gourbeyre
authors.affiliation: INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France; Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Parry
authors.affiliation: INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France; Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
authors.forename: Wafa
authors.initials: W
authors.lastname: B'Chir
authors.affiliation: INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France; Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Muranishi
authors.affiliation: INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France; Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Jousse
authors.affiliation: INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France; Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Bruhat
authors.affiliation: INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France; Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France.
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Maurin
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Proud
authors.affiliation: INRA, UMR 1019 Nutrition Humaine, Centre de Clermont-Ferrand-Theix, F-63122 Saint Genès Champanelle, France; Université Clermont 1, UFR Médecine, UMR 1019 Nutrition Humaine, Clermont-Ferrand, France. Electronic address: pierre.fafournoux@clermont.inra.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fafournoux
mesh_terms: D000596:Amino Acids / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D007930:Leucine / Q000378:metabolism* / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins; D007930:Leucine; D020123:Sirolimus
keywords: Amino acids; Leucine; Lysosome; Rags; mTORC1