mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation

Mol Cell. 2015 Jan 22;57(2):207-18. doi: 10.1016/j.molcel.2014.11.013. Epub 2014 Dec 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Autophagy-Related Proteins
  • Cell Proliferation
  • Class III Phosphatidylinositol 3-Kinases / metabolism
  • Endosomes / enzymology*
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice, Nude
  • Multiprotein Complexes / physiology*
  • Neoplasm Transplantation
  • Phagosomes / enzymology*
  • Phosphorylation
  • Protein Processing, Post-Translational*
  • TOR Serine-Threonine Kinases / physiology*
  • Tumor Suppressor Proteins / metabolism*
  • rab GTP-Binding Proteins / metabolism

Substances

  • Autophagy-Related Proteins
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • Tumor Suppressor Proteins
  • UVRAG protein, human
  • rundataxin protein, human
  • rab7 protein
  • TOR Serine-Threonine Kinases
  • Class III Phosphatidylinositol 3-Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • rab GTP-Binding Proteins