Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex

Science. 2017 Mar 24;355(6331):1306-1311. doi: 10.1126/science.aag1417.

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that becomes activated at the lysosome in response to nutrient cues. Here, we identify cholesterol, an essential building block for cellular growth, as a nutrient input that drives mTORC1 recruitment and activation at the lysosomal surface. The lysosomal transmembrane protein, SLC38A9, is required for mTORC1 activation by cholesterol through conserved cholesterol-responsive motifs. Moreover, SLC38A9 enables mTORC1 activation by cholesterol independently from its arginine-sensing function. Conversely, the Niemann-Pick C1 (NPC1) protein, which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function. Thus, lysosomal cholesterol drives mTORC1 activation and growth signaling through the SLC38A9-NPC1 complex.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Transport Systems / genetics
  • Amino Acid Transport Systems / metabolism*
  • Animals
  • Biological Transport
  • CHO Cells
  • Carrier Proteins / metabolism*
  • Cholesterol / metabolism*
  • Cholesterol, HDL / metabolism
  • Cricetulus
  • Enzyme Activation
  • Fibroblasts
  • HEK293 Cells
  • Humans
  • Lysosomes / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes / antagonists & inhibitors
  • Multiprotein Complexes / metabolism*
  • Mutation
  • Nuclear Proteins / metabolism*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Amino Acid Transport Systems
  • Carrier Proteins
  • Cholesterol, HDL
  • Multiprotein Complexes
  • Nuclear Proteins
  • PICk1 protein, human
  • SLC38A9 protein, human
  • Cholesterol
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases