2. Academic Validation
  3. Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex

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.
Brian M Castellano 1 2,  Ashley M Thelen 1 2,  Ofer Moldavski 1 2,  McKenna Feltes 3,  Reini E N van der Welle 1 2,  Laurel Mydock-McGrane 4,  Xuntian Jiang 3,  Robert J van Eijkeren 1 2,  Oliver B Davis 1 2,  Sharon M Louie 1 5,  Rushika M Perera 6,  Douglas F Covey 4,  Daniel K Nomura 1 5,  Daniel S Ory 3,  Roberto Zoncu 7 2
Affiliations

Affiliations

  • 1 Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.
  • 2 The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA 94720, USA.
  • 3 Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 4 Department of Developmental Biology and Biochemistry, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 5 Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley, CA 94720, USA.
  • 6 Department of Anatomy, Department of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 7 Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA. [email protected].
PMID: 28336668 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.

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