1. Lysosomal cholesterol activates mTORC1 via an SLC38A9–Niemann-Pick C1 signaling complex
- Author
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Castellano, Brian M, Thelen, Ashley M, Moldavski, Ofer, Feltes, McKenna, van der Welle, Reini EN, Mydock-McGrane, Laurel, Jiang, Xuntian, van Eijkeren, Robert J, Davis, Oliver B, Louie, Sharon M, Perera, Rushika M, Covey, Douglas F, Nomura, Daniel K, Ory, Daniel S, and Zoncu, Roberto
- Subjects
Underpinning research ,1.1 Normal biological development and functioning ,Amino Acid Motifs ,Amino Acid Transport Systems ,Animals ,Biological Transport ,CHO Cells ,Carrier Proteins ,Cholesterol ,Cholesterol ,HDL ,Cricetulus ,Enzyme Activation ,Fibroblasts ,HEK293 Cells ,Humans ,Lysosomes ,Mechanistic Target of Rapamycin Complex 1 ,Mice ,Multiprotein Complexes ,Mutation ,Nuclear Proteins ,Signal Transduction ,TOR Serine-Threonine Kinases ,General Science & Technology - 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.
- Published
- 2017