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Regulation of TFEB and V-ATPases by mTORC1.

The EMBO journal | 2011

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.

Pubmed ID: 21804531 RIS Download

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Associated grants

  • Agency: NINDS NIH HHS, United States
    Id: K08 NS051843-05
  • Agency: NIBIB NIH HHS, United States
    Id: F31 EB005556
  • Agency: NINDS NIH HHS, United States
    Id: K08NS051843
  • Agency: NCI NIH HHS, United States
    Id: F32 CA136087
  • Agency: NCI NIH HHS, United States
    Id: P30 CA142543
  • Agency: NIBIB NIH HHS, United States
    Id: EB 05556
  • Agency: NCI NIH HHS, United States
    Id: R01 CA129387
  • Agency: PHS HHS, United States
    Id: 77253
  • Agency: NCI NIH HHS, United States
    Id: 1P30CA142543
  • Agency: NINDS NIH HHS, United States
    Id: K08 NS051843
  • Agency: NCI NIH HHS, United States
    Id: R01CA129387
  • Agency: NCI NIH HHS, United States
    Id: R01 CA129387-05
  • Agency: NCI NIH HHS, United States
    Id: T32 CA124334

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