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

doi:10.1126/science.abg6621

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

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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.

Original language	English
Pages (from-to)	1290-1298
Number of pages	9
Journal	Science
Volume	377
Issue number	6612
DOIs	https://doi.org/10.1126/science.abg6621
State	Published - Sep 16 2022

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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. (2022). Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1. Science, 377(6612), 1290-1298. https://doi.org/10.1126/science.abg6621

@article{9fb1a5e495844603a617a082af63a5c0,

title = "Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1",

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.",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved.",

year = "2022",

month = sep,

day = "16",

doi = "10.1126/science.abg6621",

language = "English",

volume = "377",

pages = "1290--1298",

journal = "Science",

issn = "0036-8075",

number = "6612",

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Shin, HR, Citron, YR, Wang, L, Tribouillard, L, Goul, CS, Stipp, R, Sugasawa, Y, Jain, A, Samson, N, Lim, CY, Davis, OB, Castaneda-Carpio, D, Qian, M, Nomura, DK, Perera, RM, Park, E, Covey, DF, Laplante, M, Evers, AS & Zoncu, R 2022, 'Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1', Science, vol. 377, no. 6612, pp. 1290-1298. https://doi.org/10.1126/science.abg6621

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

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.

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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 -

Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1

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