title: MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB.
abstract: The mammalian target of rapamycin (MTOR) protein kinase complex is a key component of a pathway that regulates cell growth and proliferation in response to energy levels, hypoxia, nutrients and insulin. Inhibition of MTORC1 strongly induces autophagy by regulating the activity of the ULK protein kinase complex that is required for the formation of autophagosomes. However, the participation of MTORC1 in the expression of autophagy genes has not been characterized. Here we show that MTORC1 regulates nuclear localization and activity of the transcription factor EB (TFEB), a member of the bHLH leucine-zipper family of transcription factors that drives expression of autophagy and lysosomal genes. Under normal nutrient conditions, TFEB is phosphorylated in Ser211 in an MTORC1-dependent manner. This phosphorylation promotes association of TFEB with members of the YWHA (14-3-3) family of proteins and retention of the transcription factor in the cytosol. Pharmacological or genetic inhibition of MTORC1 causes dissociation of the TFEB/YWHA complex and rapid transport of TFEB to the nucleus where it increases transcription of multiple genes implicated in autophagy and lysosomal function. Active TFEB also associates with late endosomal/lysosomal membranes through interaction with the LAMTOR/RRAG/MTORC1 complex. Our results unveil a novel role for MTORC1 in the maintenance of cellular homeostasis by regulating autophagy at the transcriptional level.
authors.affiliation: Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD USA.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martina
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Marjan
authors.initials: M
authors.lastname: Gucek
authors.forename: Rosa
authors.initials: R
authors.lastname: Puertollano
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000595:Amino Acid Sequence; D001343:Autophagy / Q000235:genetics*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008954:Models, Biological; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D010588:Phagosomes / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic
chemical_list: D048948:14-3-3 Proteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D046912:Multiprotein Complexes; D011506:Proteins; C064972:TFEB protein, human; D010768:Phosphoserine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases