Multistep regulation of TFEB by MTORC1

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, TFEBS211A 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.

Keywords: Lysosomal biogenesis; MTOR; TFEB; YWHA; subcellular localization.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • HeLa Cells
  • Humans
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mice
  • Models, Biological
  • Naphthyridines / pharmacology
  • Organelle Biogenesis
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism
  • Protein Transport / drug effects


  • 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Naphthyridines
  • TFEB protein, human
  • Tcfeb protein, mouse
  • Phosphoserine
  • Mechanistic Target of Rapamycin Complex 1