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 inhibits mTORC1 signaling through its sterol transport function. Thus, lysosomal cholesterol drives mTORC1 activation and growth signaling through the SLC38A9-NPC1 complex.
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.|The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA 94720, USA.
Brian M
0000-0001-6545-6429
BM
Castellano
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.|The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA 94720, USA.
Ashley M
0000-0002-1406-0691
AM
Thelen
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.|The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA 94720, USA.
Ofer
O
Moldavski
Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
McKenna
0000-0002-4178-8055
M
Feltes
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.|The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA 94720, USA.
Reini E N
RE
van der Welle
Department of Developmental Biology and Biochemistry, Washington University School of Medicine, St. Louis, MO 63110, USA.
Laurel
0000-0002-2651-0848
L
Mydock-McGrane
Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Xuntian
X
Jiang
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.|The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA 94720, USA.
Robert J
0000-0002-0443-299X
RJ
van Eijkeren
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.|The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA 94720, USA.
Oliver B
OB
Davis
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.|Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley, CA 94720, USA.
Sharon M
0000-0002-9368-1225
SM
Louie
Department of Anatomy, Department of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Rushika M
RM
Perera
Department of Developmental Biology and Biochemistry, Washington University School of Medicine, St. Louis, MO 63110, USA.
Douglas F
0000-0002-9316-8683
DF
Covey
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.|Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley, CA 94720, USA.
Daniel K
DK
Nomura
Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Daniel S
DS
Ory
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA. rzoncu@berkeley.edu.|The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA 94720, USA.
Roberto
0000-0003-1611-1891
R
Zoncu
D020816:Amino Acid Motifs; D026905:Amino Acid Transport Systems / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D003412:Cricetulus; D004789:Enzyme Activation; D005347:Fibroblasts; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D026905:Amino Acid Transport Systems; D002352:Carrier Proteins; D008076:Cholesterol, HDL; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; C498297:PICk1 protein, human; C000594592:SLC38A9 protein, human; D002784:Cholesterol; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases