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

Brian M. Castellano, Ashley M. Thelen, Ofer Moldavski, McKenna Feltes, Reini E.N. Van Der Welle, Laurel Mydock-McGrane, Xuntian Jiang, Robert J. Van Eijkeren, Oliver B. Davis, Sharon M. Louie, Rushika M. Perera, Douglas F. Covey, Daniel K. Nomura, Daniel S. Ory, Roberto Zoncu

Research output: Contribution to journalArticlepeer-review

227 Scopus citations

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.

Original languageEnglish
Pages (from-to)1306-1311
Number of pages6
JournalScience
Volume355
Issue number6331
DOIs
StatePublished - Mar 24 2017

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