TY - JOUR
T1 - Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex
AU - Castellano, Brian M.
AU - Thelen, Ashley M.
AU - Moldavski, Ofer
AU - Feltes, McKenna
AU - Van Der Welle, Reini E.N.
AU - Mydock-McGrane, Laurel
AU - Jiang, Xuntian
AU - Van Eijkeren, Robert J.
AU - Davis, Oliver B.
AU - Louie, Sharon M.
AU - Perera, Rushika M.
AU - Covey, Douglas F.
AU - Nomura, Daniel K.
AU - Ory, Daniel S.
AU - Zoncu, Roberto
N1 - Funding Information:
This work was supported by the NIH Director's New Innovator Award (1DP2CA195761-01), the Pew-Stewart Scholarship for Cancer Research, the Damon Runyon-Rachleff Innovation Award, and the Edward Mallinckrodt, Jr. Foundation Grant to R.Z.; National Institutes of Health grant R01 HL067773 to D.S.O. and D.F.C.; the Taylor Family Institute for Innovative Psychiatric Research to D.F.C.; and a National Science Foundation Graduate Research Fellowship (DGE 1106400) to A.M.T.
PY - 2017/3/24
Y1 - 2017/3/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85016302146&partnerID=8YFLogxK
U2 - 10.1126/science.aag1417
DO - 10.1126/science.aag1417
M3 - Article
C2 - 28336668
AN - SCOPUS:85016302146
SN - 0036-8075
VL - 355
SP - 1306
EP - 1311
JO - Science
JF - Science
IS - 6331
ER -