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Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1

Shin, Hijai R., Citron, Y. Rose, Wang, Lei, Tribouillard, Laura, Goul, Claire S., Stipp, Robin, Sugasawa, Yusuke, Jain, Aakriti, Samson, Nolwenn, Lim, Chun-Yan, Davis, Oliver B., Castaneda-Carpio, David, Qian, Mingxing, Nomura, Daniel K., Perera, Rushika M., Park, Eunyong, Covey, Douglas F., Laplante, Mathieu, Evers, Alex S., Zoncu, Roberto·2022·Science
DOI 10.1126/science.abg6621PMC PMC10023259
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Abstract

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.

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Metadata

Authors
Shin, H. R., Citron, Y. R., Wang, L., Tribouillard, L., Goul, C. S., Stipp, R., Sugasawa, Y., Jain, A., Samson, N., Lim, C.-Y., Davis, O. B., Castaneda-Carpio, D., Qian, M., Nomura, D. K., Perera, R. M., Park, E., Covey, D. F., Laplante, M., Evers, A. S., & Zoncu, R.
Affiliations
  • Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.
  • Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Centre de recherche sur le cancer de l’Université Laval, Université Laval, Québec, QC G1R 3S3, Canada.
  • Department of Anesthesiology and Pain Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
  • Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA.
  • Department of Developmental Biology and Biochemistry, Washington University School of Medicine, St. Louis, MO 63110, USA.
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-09-16
Volume
377
Issue
6612
Pages
1290-1298
ISSN
  • 0036-8075
  • 1095-9203
DOI
10.1126/science.abg6621
PMC
PMC10023259
Cited by
149
References
9
Language
en

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