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

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…

• NS
  National Science Foundation

  Award: DGE 1106400
• EM
  Edward Mallinckrodt, Jr. Foundation
• NI
  National Institutes of Health

  Awards: R01 HL067773, 1DP2CA195761-01
• TF
  Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis