title: mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation.
abstract: mTORC1 plays a key role in autophagy as a negative regulator. The currently known targets of mTORC1 in the autophagy pathway mainly function at early stages of autophagosome formation. Here, we identify that mTORC1 inhibits later stages of autophagy by phosphorylating UVRAG. Under nutrient-enriched conditions, mTORC1 binds and phosphorylates UVRAG. The phosphorylation positively regulates the association of UVRAG with RUBICON, thereby enhancing the antagonizing effect of RUBICON on UVRAG-mediated autophagosome maturation. Upon dephosphorylation, UVRAG is released from RUBICON to interact with the HOPS complex, a component for the late endosome and lysosome fusion machinery, and enhances autophagosome and endosome maturation. Consequently, the dephosphorylation of UVRAG facilitates the lysosomal degradation of epidermal growth factor receptor (EGFR), reduces EGFR signaling, and suppresses cancer cell proliferation and tumor growth. These results demonstrate that mTORC1 engages in late stages of autophagy and endosome maturation, defining a broader range of mTORC1 functions in the membrane-associated processes.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Division of Metabolism and Functionality Research, Korea Food Research Institute, 463-746, Republic of Korea.
authors.forename: Chang Hwa
authors.initials: CH
authors.lastname: Jung
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Minchul
authors.initials: M
authors.lastname: Seo
authors.affiliation: Department of Pharmacology, Pusan National University, Pusan, 626-870, Republic of Korea.
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Ji-Man
authors.initials: JM
authors.lastname: Park
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pharmacology, Pusan National University, Pusan, 626-870, Republic of Korea.
authors.forename: Sun Sik
authors.initials: SS
authors.lastname: Bae
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: dhkim@umn.edu.
authors.forename: Do-Hyung
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000071183:Autophagy-Related Proteins; D049109:Cell Proliferation; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011992:Endosomes / Q000201:enzymology*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000502:physiology*; D009368:Neoplasm Transplantation; D010588:Phagosomes / Q000201:enzymology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D000071183:Autophagy-Related Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; C552537:RUBCN protein, human; D025521:Tumor Suppressor Proteins; C408122:UVRAG protein, human; D000090802:rab7 GTP-Binding Proteins; D058546:Class III Phosphatidylinositol 3-Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020691:rab GTP-Binding Proteins