title: Regulation of TFEB and V-ATPases by mTORC1.
abstract: Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is an important, highly conserved, regulator of cell growth. Ancient among the signals that regulate mTORC1 are nutrients. Amino acids direct mTORC1 to the surface of the late endosome/lysosome, where mTORC1 becomes receptive to other inputs. However, the interplay between endosomes and mTORC1 is poorly understood. Here, we report the discovery of a network that links mTORC1 to a critical component of the late endosome/lysosome, the V-ATPase. In an unbiased screen, we found that mTORC1 regulated the expression of, among other lysosomal genes, the V-ATPases. mTORC1 regulates V-ATPase expression both in cells and in mice. V-ATPase regulation by mTORC1 involves a transcription factor translocated in renal cancer, TFEB. TFEB is required for the expression of a large subset of mTORC1 responsive genes. mTORC1 coordinately regulates TFEB phosphorylation and nuclear localization and in a manner dependent on both TFEB and V-ATPases, mTORC1 promotes endocytosis. These data uncover a regulatory network linking an oncogenic transcription factor that is a master regulator of lysosomal biogenesis, TFEB, to mTORC1 and endocytosis.
authors.affiliation: Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Peña-Llopis
authors.forename: Silvia
authors.initials: S
authors.lastname: Vega-Rubin-de-Celis
authors.forename: Jacob C
authors.initials: JC
authors.lastname: Schwartz
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Wolff
authors.forename: Tram Anh T
authors.initials: TA
authors.lastname: Tran
authors.forename: Lihua
authors.initials: L
authors.lastname: Zou
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.forename: David R
authors.initials: DR
authors.lastname: Corey
authors.forename: James
authors.initials: J
authors.lastname: Brugarolas
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology*; D002461:Cell Line, Transformed / Q000187:drug effects / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D004790:Enzyme Induction / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D008247:Lysosomes / Q000201:enzymology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011506:Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000502:physiology; D025262:Vacuolar Proton-Translocating ATPases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011506:Proteins; C484068:Tcfeb protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D003609:Dactinomycin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D025262:Vacuolar Proton-Translocating ATPases; D020123:Sirolimus