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

doi:10.1038/emboj.2011.257

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Regulation of TFEB and V-ATPases by mTORC1

Journal article

Open access

Peer reviewed

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 and James Brugarolas

The EMBO journal, Vol.30(16), pp.3242-3258

07/29/2011

DOI: 10.1038/emboj.2011.257

PMCID: PMC3160667

PMID: 21804531

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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.

Vacuolar Proton-Translocating ATPases - genetics

Phosphorylation

Multiprotein Complexes

Lysosomes - enzymology

Protein Transport - physiology

Protein Transport - drug effects

Cell Line, Transformed - drug effects

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - physiology

Mechanistic Target of Rapamycin Complex 1

Vacuolar Proton-Translocating ATPases - biosynthesis

Vacuolar Proton-Translocating ATPases - physiology

Enzyme Induction - drug effects

Fibroblasts - metabolism

Proteins - physiology

Endocytosis - drug effects

Gene Expression Regulation

Sirolimus - pharmacology

Amino Acid Motifs

Endocytosis - physiology

Tumor Suppressor Proteins - physiology

Animals

MAP Kinase Signaling System - drug effects

Fibroblasts - drug effects

Cell Line, Transformed - metabolism

Signal Transduction - physiology

Mice

Protein Kinase Inhibitors - pharmacology

Protein Processing, Post-Translational

TOR Serine-Threonine Kinases

Dactinomycin - pharmacology

Details

Title: Subtitle: Regulation of TFEB and V-ATPases by mTORC1
Creators: Samuel Peña-Llopis - Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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
Resource Type: Journal article
Publication Details: The EMBO journal, Vol.30(16), pp.3242-3258
DOI: 10.1038/emboj.2011.257
PMID: 21804531
PMCID: PMC3160667
NLM abbreviation: EMBO J
ISSN: 1460-2075
eISSN: 1460-2075
Publisher: England
Grant note: 77253 / PHS HHS EB 05556 / NIBIB NIH HHS F31 EB005556 / NIBIB NIH HHS K08 NS051843-05 / NINDS NIH HHS F32 CA136087 / NCI NIH HHS R01 CA129387-05 / NCI NIH HHS K08 NS051843 / NINDS NIH HHS R01 CA129387 / NCI NIH HHS R01CA129387 / NCI NIH HHS P30 CA142543 / NCI NIH HHS 1P30CA142543 / NCI NIH HHS T32 CA124334 / NCI NIH HHS K08NS051843 / NINDS NIH HHS
Language: English
Date published: 07/29/2011
Academic Unit: Preventive and Community Dentistry; Biostatistics; Dental Research
Record Identifier: 9983917770302771

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