Regulation of TFEB and V-ATPases by mTORC1

EMBO J. 2011 Jul 29;30(16):3242-58. doi: 10.1038/emboj.2011.257.

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.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / physiology*
  • Cell Line, Transformed / drug effects
  • Cell Line, Transformed / metabolism
  • Dactinomycin / pharmacology
  • Endocytosis / drug effects
  • Endocytosis / physiology*
  • Enzyme Induction / drug effects
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Regulation
  • Lysosomes / enzymology
  • MAP Kinase Signaling System / drug effects
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Processing, Post-Translational*
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • Proteins / physiology*
  • Signal Transduction / physiology
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / physiology
  • Vacuolar Proton-Translocating ATPases / biosynthesis
  • Vacuolar Proton-Translocating ATPases / genetics
  • Vacuolar Proton-Translocating ATPases / physiology*

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Multiprotein Complexes
  • Protein Kinase Inhibitors
  • Proteins
  • Tcfeb protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Dactinomycin
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Vacuolar Proton-Translocating ATPases
  • Sirolimus

Associated data

  • GEO/GSE27982
  • GEO/GSE28021