한빛사 논문
Hijai R. Shin1,2, Y. Rose Citron1,2†, Lei Wang3†‡, Laura Tribouillard4, Claire S. Goul1,2, Robin Stipp1,2, Yusuke Sugasawa5, Aakriti Jain1,2, Nolwenn Samson4, Chun-Yan Lim1,2, Oliver B. Davis1,2, David Castaneda-Carpio1,2, Mingxing Qian6, Daniel K. Nomura1,7, Rushika M. Perera8, Eunyong Park1, Douglas F. Covey9,10, Mathieu Laplante4, Alex S. Evers3,9,10, Roberto Zoncu1,2*
1Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA. 2Innovative Genomics Initiative at the University of California, Berkeley, Berkeley, CA 94720, USA. 3Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA. 4Centre de recherche sur le cancer de l’Université Laval, Université Laval, Québec, QC G1R 3S3, Canada. 5Department of Anesthesiology and Pain Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan. 6Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. 7Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley, CA 94720, USA. 8Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA. 9Department of Developmental Biology and Biochemistry, Washington University School of Medicine, St. Louis, MO 63110, USA. 10The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
*Corresponding author.
†These authors contributed equally to this work.
‡Present address: Department of Anesthesiology, Union Hospital,
Tongji Medical College, Huazhong University of Science and
Technology, Wuhan, Hubei 430022, China.
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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