Vega-Rubin-de-Celis Silvia, Peña-Llopis Samuel, Konda Meghan, Brugarolas James
a Kidney Cancer Program, Simmons Comprehensive Cancer Center , University of Texas Southwestern Medical Center , Dallas , TX , USA.
b Department of Internal Medicine, Hematology/Oncology Division , University of Texas Southwestern Medical Center , Dallas , TX , USA.
Autophagy. 2017 Mar 4;13(3):464-472. doi: 10.1080/15548627.2016.1271514. Epub 2017 Jan 5.
The master regulator of lysosome biogenesis, TFEB, is regulated by MTORC1 through phosphorylation at S211, and a S211A mutation increases nuclear localization. However, TFEB localizes diffusely in both cytoplasm and nucleus and, as we show, retains regulation by MTORC1. Here, we report that endogenous TFEB is phosphorylated at S122 in an MTORC1-dependent manner, that S122 is phosphorylated in vitro by recombinant MTOR, and that S122 is important for TFEB regulation by MTORC1. Specifically, nuclear localization following MTORC1 inhibition is blocked by a S122D mutation (despite S211 dephosphorylation). Furthermore, such a mutation inhibits lysosomal biogenesis induced by Torin1. These data reveal a novel mechanism of TFEB regulation by MTORC1 essential for lysosomal biogenesis.
溶酶体生物发生的主要调节因子TFEB通过S211位点的磷酸化受mTORC1调控，S211A突变会增加其核定位。然而，TFEB在细胞质和细胞核中均呈弥散分布，并且如我们所展示的，它仍受mTORC1调控。在此，我们报告内源性TFEB在S122位点以mTORC1依赖的方式被磷酸化，S122在体外可被重组mTOR磷酸化，且S122对于mTORC1对TFEB的调控很重要。具体而言，mTORC1抑制后的核定位会被S122D突变阻断（尽管S211去磷酸化）。此外，这种突变会抑制Torin1诱导的溶酶体生物发生。这些数据揭示了mTORC1对TFEB调控的一种新机制，这对于溶酶体生物发生至关重要。
