A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB

EMBO J. 2012 Mar 7;31(5):1095-108. doi: 10.1038/emboj.2012.32. Epub 2012 Feb 17.

Abstract

The lysosome plays a key role in cellular homeostasis by controlling both cellular clearance and energy production to respond to environmental cues. However, the mechanisms mediating lysosomal adaptation are largely unknown. Here, we show that the Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane. When nutrients are present, phosphorylation of TFEB by mTORC1 inhibits TFEB activity. Conversely, pharmacological inhibition of mTORC1, as well as starvation and lysosomal disruption, activates TFEB by promoting its nuclear translocation. In addition, the transcriptional response of lysosomal and autophagic genes to either lysosomal dysfunction or pharmacological inhibition of mTORC1 is suppressed in TFEB-/- cells. Interestingly, the Rag GTPase complex, which senses lysosomal amino acids and activates mTORC1, is both necessary and sufficient to regulate starvation- and stress-induced nuclear translocation of TFEB. These data indicate that the lysosome senses its content and regulates its own biogenesis by a lysosome-to-nucleus signalling mechanism that involves TFEB and mTOR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Cell Line
  • Cell Nucleus / physiology*
  • Humans
  • Immunoprecipitation
  • Lysosome-Associated Membrane Glycoproteins / metabolism
  • Lysosomes / metabolism
  • Lysosomes / physiology*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Models, Biological
  • Multiprotein Complexes
  • Protein Binding
  • Protein Interaction Mapping
  • Proteins / metabolism*
  • Signal Transduction*
  • TOR Serine-Threonine Kinases

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Lysosome-Associated Membrane Glycoproteins
  • Multiprotein Complexes
  • Proteins
  • TFEB protein, human
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1