TY - JOUR
T1 - Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1
AU - Shin, Hijai R.
AU - Citron, Y. Rose
AU - Wang, Lei
AU - Tribouillard, Laura
AU - Goul, Claire S.
AU - Stipp, Robin
AU - Sugasawa, Yusuke
AU - Jain, Aakriti
AU - Samson, Nolwenn
AU - Lim, Chun Yan
AU - Davis, Oliver B.
AU - Castaneda-Carpio, David
AU - Qian, Mingxing
AU - Nomura, Daniel K.
AU - Perera, Rushika M.
AU - Park, Eunyong
AU - Covey, Douglas F.
AU - Laplante, Mathieu
AU - Evers, Alex S.
AU - Zoncu, Roberto
N1 - Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved.
PY - 2022/9/16
Y1 - 2022/9/16
N2 - Lysosomes coordinate cellular metabolism and growth upon sensing of essential nutrients, including cholesterol. Through bioinformatic analysis of lysosomal proteomes, we identified lysosomal cholesterol signaling (LYCHOS, previously annotated as G protein–coupled receptor 155), a multidomain transmembrane protein that enables cholesterol-dependent activation of the master growth regulator, the protein kinase mechanistic target of rapamycin complex 1 (mTORC1). Cholesterol bound to the amino-terminal permease-like region of LYCHOS, and mutating this site impaired mTORC1 activation. At high cholesterol concentrations, LYCHOS bound to the GATOR1 complex, a guanosine triphosphatase (GTPase)–activating protein for the Rag GTPases, through a conserved cytoplasm-facing loop. By sequestering GATOR1, LYCHOS promotes cholesterol- and Rag-dependent recruitment of mTORC1 to lysosomes. Thus, LYCHOS functions in a lysosomal pathway for cholesterol sensing and couples cholesterol concentrations to mTORC1-dependent anabolic signaling.
AB - Lysosomes coordinate cellular metabolism and growth upon sensing of essential nutrients, including cholesterol. Through bioinformatic analysis of lysosomal proteomes, we identified lysosomal cholesterol signaling (LYCHOS, previously annotated as G protein–coupled receptor 155), a multidomain transmembrane protein that enables cholesterol-dependent activation of the master growth regulator, the protein kinase mechanistic target of rapamycin complex 1 (mTORC1). Cholesterol bound to the amino-terminal permease-like region of LYCHOS, and mutating this site impaired mTORC1 activation. At high cholesterol concentrations, LYCHOS bound to the GATOR1 complex, a guanosine triphosphatase (GTPase)–activating protein for the Rag GTPases, through a conserved cytoplasm-facing loop. By sequestering GATOR1, LYCHOS promotes cholesterol- and Rag-dependent recruitment of mTORC1 to lysosomes. Thus, LYCHOS functions in a lysosomal pathway for cholesterol sensing and couples cholesterol concentrations to mTORC1-dependent anabolic signaling.
UR - http://www.scopus.com/inward/record.url?scp=85137824250&partnerID=8YFLogxK
U2 - 10.1126/science.abg6621
DO - 10.1126/science.abg6621
M3 - Article
C2 - 36007018
AN - SCOPUS:85137824250
SN - 0036-8075
VL - 377
SP - 1290
EP - 1298
JO - Science
JF - Science
IS - 6612
ER -