Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1

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

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish
Pages (from-to)1290-1298
Number of pages9
JournalScience
Volume377
Issue number6612
DOIs
StatePublished - Sep 16 2022

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