Regulation of TFEB and V-ATPases by mTORC1

被引:373
作者
Pena-Llopis, Samuel [1 ,2 ,3 ]
Vega-Rubin-de-Celis, Silvia [1 ,2 ,3 ]
Schwartz, Jacob C. [4 ]
Wolff, Nicholas C. [1 ,2 ,3 ]
Tran, Tram Anh T. [1 ,2 ,3 ]
Zou, Lihua [5 ]
Xie, Xian-Jin [3 ]
Corey, David R. [4 ]
Brugarolas, James [1 ,2 ,3 ]
机构
[1] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Oncol, Dallas, TX 75390 USA
[2] Univ Texas SW Med Ctr Dallas, Dept Dev Biol, Dallas, TX 75390 USA
[3] Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA
[4] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA
[5] Broad Inst Harvard & MIT, Canc Program, Cambridge, MA USA
关键词
autophagy; lysosome; microarray; RCC; Tefeb; TUBEROUS SCLEROSIS COMPLEX; TUMOR-SUPPRESSOR COMPLEX; MAMMALIAN TARGET; CELL-GROWTH; BINDING PARTNER; RAPAMYCIN TOR; UP-REGULATION; GENE-PRODUCT; RAG GTPASES; H+-ATPASE;
D O I
10.1038/emboj.2011.257
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. The EMBO Journal (2011) 30, 3242-3258. doi:10.1038/emboj.2011.257; Published online 29 July 2011
引用
收藏
页码:3242 / 3258
页数:17
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