Regulation of TFEB and V-ATPases by mTORC1

Samuel Peña-Llopis, Silvia Vega-Rubin-De-Celis, Jacob C. Schwartz, Nicholas C. Wolff, Tram Anh T Tran, Lihua Zou, Xian Jin Xie, David R. Corey, James Brugarolas

Research output: Contribution to journalArticle

241 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3242-3258
Number of pages17
JournalEMBO Journal
Volume30
Issue number16
DOIs
Publication statusPublished - Aug 17 2011

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Keywords

  • autophagy
  • lysosome
  • microarray
  • RCC
  • Tcfeb

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Medicine(all)

Cite this

Peña-Llopis, S., Vega-Rubin-De-Celis, S., Schwartz, J. C., Wolff, N. C., Tran, T. A. T., Zou, L., ... Brugarolas, J. (2011). Regulation of TFEB and V-ATPases by mTORC1. EMBO Journal, 30(16), 3242-3258. https://doi.org/10.1038/emboj.2011.257