Journal Article

Regulation of TFEB and V-ATPases by mTORC1

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

2011

Overview

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. TORC1 is a key regulator of cell growth in response to nutrients and acts at the surface of the late endosome. This study identifies V‐ATPase genes as transcriptional targets of TORC1 and implicates the transcription factor TFEB as an important mediator of TORC1‐dependent gene expression and TORC1‐regulated endocytosis.

• Publisher: John Wiley & Sons, Ltd,Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: Amino Acid Motifs / Amino acids / Animals / autophagy / Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - physiology / Cell Line, Transformed - drug effects / Cell Line, Transformed - metabolism / Dactinomycin - pharmacology / EMBO20 / EMBO37 / Endocytosis / Endocytosis - drug effects / Endocytosis - physiology / Enzyme Induction - drug effects / Fibroblasts - drug effects / Fibroblasts - metabolism / Gene expression / Gene Expression Regulation / lysosome / Lysosomes - enzymology / Mammals / MAP Kinase Signaling System - drug effects / Mechanistic Target of Rapamycin Complex 1 / Mice / microarray / Molecular biology / Multiprotein Complexes / Nutrients / Phosphorylation / Protein Kinase Inhibitors - pharmacology / Protein Processing, Post-Translational / Protein Transport - drug effects / Protein Transport - physiology / Proteins / Proteins - physiology / RCC / Signal transduction / Signal Transduction - physiology / Sirolimus - pharmacology / Tcfeb / 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