Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
EMBO J. 2011 Jul 29;30(16):3242-58. doi: 10.1038/emboj.2011.257.
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.
哺乳动物雷帕霉素靶蛋白（mTOR）复合物 1（mTORC1）是细胞生长的重要且高度保守的调节因子。在调节 mTORC1 的众多信号中，古老的信号是营养物质。氨基酸将 mTORC1 引导到晚期内体/溶酶体的表面，在那里 mTORC1 对其他输入变得敏感。然而，内体和 mTORC1 之间的相互作用知之甚少。在这里，我们报告了一个将 mTORC1 与晚期内体/溶酶体的关键组成部分——V-ATPase 联系起来的网络的发现。在一项无偏见的筛选中，我们发现 mTORC1 调节了溶酶体基因中除其他基因外的 V-ATPase 的表达。mTORC1 在细胞和小鼠中都调节 V-ATPase 的表达。mTORC1 对 V-ATPase 的调节涉及到一种在肾细胞癌中易位的转录因子 TFEB。TFEB 是 mTORC1 响应基因的一大子集表达所必需的。mTORC1 协调调节 TFEB 的磷酸化和核定位，并且以依赖于 TFEB 和 V-ATPase 的方式，mTORC1 促进内吞作用。这些数据揭示了一个调节网络，将一种致癌转录因子（TFEB）与 mTORC1 和内吞作用联系起来，TFEB 是溶酶体生物发生的主要调节因子。
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