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 - Funding Information:
We thank R. Irannejad, J. Thorner, and all the members of the Zoncu lab for critical reading of the manuscript. We thank M. Rape for providing endogenously tagged 3xFLAG KLH12 HEK293T cells, R. Irannejad for the Gi/Gs/Gq cDNA constructs, the Stroud lab for the anti-GFP nanobody Sepharose, and T. Wu in the Gestwicki lab for assistance with the DSF experiment. This work was supported by NIH R01GM127763, a University of Notre Dame/ APMRF grant, an Edward Mallinckrodt Jr. Foundation Scholar Award to R.Z., a 2019 AACR-Amgen Fellowship in Clinical/ Translational Cancer Research (19-40-11-SHIN) and a 2021 AFTDHolloway postdoctoral fellowship (2021-002) to H.R.S., NIH R01MH110550, NIH R01HL067773 to D.F.C., NIH R01GM108799 to A.S.E., and 1P50MH122379 to D.F.C and A.S.E.
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 -