Lysosomal cholesterol activates mTORC1 via an SLC38A9–Niemann-Pick C1 signaling complex
Open accessAbstract
The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that becomes activated at the lysosome in response to nutrient cues. Here, we identify cholesterol, an essential building block for cellular growth, as a nutrient input that drives mTORC1 recruitment and activation at the lysosomal surface. The lysosomal transmembrane protein, SLC38A9, is required for mTORC1 activation by cholesterol through conserved cholesterol-responsive motifs. Moreover, SLC38A9 enables mTORC1 activation by cholesterol independently from its arginine-sensing function. Conversely, the Niemann-Pick C1 (NPC1) protein, which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function. Thus, lysosomal cholesterol drives mTORC1 activation and growth signaling through the SLC38A9-NPC1 complex.
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Comparisons of circulating testosterone between vegans and omnivores have revealed no differences.
“and comparisons of circulating testosterone between vegans and omnivores have revealed no differences [132].”
From Nutritional Considerations for the Vegan Athlete (2023) · cites this paper as [132]
There is currently no evidence suggesting that vegans are deficient in the fat-soluble vitamins.
“However, there is currently no evidence suggesting that vegans are deficient in the fat-soluble vitamins, and comparisons of circulating testosterone between vegans and omnivores have revealed no differences [132].”
From Nutritional Considerations for the Vegan Athlete (2023) · cites this paper as [132]
NPC1 has been implicated in cholesterol-dependent signaling to mTORC1 through SLC38A9.
“Additionally, NPC1 has been implicated in cholesterol-dependent signaling to mTORC1 through SLC38A9 (Castellano et al., 2017)”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Castellano et al., 2017
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Amino Acids License Kinase mTORC1 Activity and Treg Cell Function via Small G Proteins Rag and Rheb
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Non-canonical mTORC1 signaling at the lysosome.
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Local cholesterol metabolism orchestrates remyelination
Berghoff, S. A., Spieth, L., & Saher, G. (2022) · Trends in Neurosciences · doi:10.1016/j.tins.2022.01.001 · Cited by 139 · see citing works
Lysosomal control of senescence and inflammation through cholesterol partitioning
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How Lysosomes Sense, Integrate, and Cope with Stress
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Lysosomal GPCR-like Protein LYCHOS Signals Cholesterol Sufficiency to mTORC1
Shin, H. R., Citron, Y. R., Wang, L., Tribouillard, L., Goul, C. S., Stipp, R., Sugasawa, Y., Jain, A., Samson, N., Lim, C.-Y., et al. (2022) · Science · doi:10.1126/science.abg6621 · Cited by 125 · see citing works
The Multifaceted Role of Nutrient Sensing and mTORC1 Signaling in Physiology and Aging
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The Role of Cholesterol in α‐Synuclein and Lewy Body Pathology in GBA1 Parkinson's Disease
García‐Sanz, P., Aerts, J. M. F. G., & Moratalla, R. (2020) · Movement Disorders · doi:10.1002/mds.28396 · Cited by 124 · see citing works
Lysosomes: Signaling Hubs for Metabolic Sensing and Longevity
Savini, M., Zhao, Q., & Wang, M. C. (2019) · Trends in Cell Biology · doi:10.1016/j.tcb.2019.08.008 · Cited by 115 · see citing works
“A recent discovery couples lysosomal cholesterol inputs with mTORC1 signaling (Figure 2) [123].”
BackgroundInfluentialThe Lysosome at the Intersection of Cellular Growth and Destruction
Shin, H. R., & Zoncu, R. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.06.010 · Cited by 112 · see citing works
Monteyne, A. J., Coelho, M. O., Porter, C., Abdelrahman, D. R., Jameson, T. S., Jackman, S. R., Blackwell, J. R., Finnigan, T. J., Stephens, F. B., Dirks, M. L., et al. (2020) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqaa092 · Cited by 110 · see citing works
Lipophagy and Lipolysis Status in Lipid Storage and Lipid Metabolism Diseases
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Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia
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Sterol transporters at membrane contact sites regulate TORC1 and TORC2 signaling
Murley, A., Yamada, J., Niles, B. J., Toulmay, A., Prinz, W., Powers, T., & Nunnari, J. (2017) · Journal of Cell Biology · doi:10.1083/jcb.201610032 · Cited by 86 · see citing works
“Thus, our data suggest that sterols play a key general role in TORC1/2 regulation, a speculation consistent with the recent finding that cholesterol regulates the recruitment and activation of mTORC1 at the lysosomal surface in mammalian cells (Castellano et al., 2017).”
BackgroundNutrient-regulated control of lysosome function by signaling lipid conversion
Ebner, M., Puchkov, D., López‐Ortega, O., Muthukottiappan, P., Su, Y., Schmied, C., Zillmann, S., Nikonenko, I., Koddebusch, J., Dornan, G. L., et al. (2023) · Cell · doi:10.1016/j.cell.2023.09.027 · Cited by 106 · see citing works
“52,65 Consistently, loss of PI4K2A restored normal PI(4)P levels (see Figure 3N) and rescued defective mTORC1 signaling caused by loss of Sac1 (Figure S6J).”
Niemann–Pick type C disease: cellular pathology and pharmacotherapy
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Nutrient-sensing mTORC1 and AMPK pathways in chronic kidney diseases
Huynh, C. Q., Ryu, J., Lee, J., Inoki, A., & Inoki, K. (2022) · Nature Reviews Nephrology · doi:10.1038/s41581-022-00648-y · Cited by 104 · see citing works
Lipoproteins and cancer: The role of HDL-C, LDL-C, and cholesterol-lowering drugs
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Dysregulation of cholesterol metabolism in cancer progression
Liu, X., Lv, M., Zhang, W., & Zhan, Q. (2023) · Oncogene · doi:10.1038/s41388-023-02836-x · Cited by 102 · see citing works
“Cholesterol in lysosomes can activate mTORC1 via the SLC38A9-NPC1 signaling pathway, inducing cancer cell proliferation, metastasis, and invasion [49].”
BackgroundKumar, S., Jain, A., Choi, S. W., da Silva, G. P. D., Allers, L., Mudd, M. H., Peters, R. S., Anonsen, J. H., Rusten, T.-E., Lazarou, M., et al. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0549-1 · Cited by 95 · see citing works
Regulation of mTORC1 by Upstream Stimuli
Melick, C. H., & Jewell, J. L. (2020) · Genes · doi:10.3390/genes11090989 · Cited by 80 · see citing works
“SLC38A9 has also been shown to play a role in mTORC1 activation by cholesterol [117].”
BackgroundLu, H., Sun, J., Liang, W., Chang, Z., Rom, O., Zhao, Y., Zhao, G., Xiong, W., Wang, H., Zhu, T., et al. (2020) · Circulation · doi:10.1161/circulationaha.119.044803 · Cited by 98 · see citing works
Allosteric enhancement of ORP1-mediated cholesterol transport by PI(4,5)P2/PI(3,4)P2
Dong, J., Du, X., Wang, H., Wang, J., Lu, C., Chen, X., Zhu, Z., Luo, Z., Yu, L., Brown, A. J., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08791-0 · Cited by 98 · see citing works
Ponsford, A. H., Ryan, T. A., Raimondi, A., Cocucci, E., Wycislo, S. A., Fröhlich, F., Swan, L. E., & Stagi, M. (2020) · Autophagy · doi:10.1080/15548627.2020.1771858 · Cited by 96 · see citing works
“[48] and SLC38A9/SNAT9 [49,50], have been found specifically on lysosomes to mediate amino acid sensing to the MTORC1 complex [51].”
BackgroundFolliculin: A Regulator of Transcription Through AMPK and mTOR Signaling Pathways
Ramírez-Reyes, J. M. J., Cuesta, R., & Pause, A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.667311 · Cited by 87 · see citing works
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Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex
Su, M.-Y., Morris, K., Kim, D. J., Fu, Y.-X., Lawrence, R., Stjepanovic, G., Zoncu, R., & Hurley, J. (2017) · Molecules and Cells · doi:10.1016/j.molcel.2017.10.016 · Cited by 90 · see citing works
“…and cholesterol, trigger the lysosomal translocation of mTORC1 via a mechanism that requires the Ras-related, heterodimeric Rag guanosine triphosphatases (GTPases) and the pentameric Ragulator complex (Bar-Peled et al., 2013; Castellano et al., 2017; Efeyan et al., 2013; Sancak et al., 2008, 2010).”
BackgroundNutrients: Signal 4 in T cell immunity
Raynor, J. L., & Chi, H. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20221839 · Cited by 94 · see citing works
“Cholesterol is sensed by SLC38A9 or lysosomal GPCR-like protein (LYCHOS) at the lysosomal surface, enabling mTORC1 activation (Castellano et al., 2017; Shin et al., 2022), but the roles of these sensors in T cell responses require investigation.”
BackgroundCD63 sorts cholesterol into endosomes for storage and distribution via exosomes
Palmulli, R., Couty, M., Piontek, M. C., Ponnaiah, M., Dingli, F., Verweij, F. J., Charrin, S., Tantucci, M., Sasidharan, S., Rubinstein, E., et al. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01432-9 · Cited by 95 · see citing works
“However, it could be crucial during starvation, aligning with the role of CD63 in autophagy 65 and probably influencing NPC1-dependent mTORC1 activity 66 or, in the context of cancer, where part of the tumour might not be reached by the blood circulation.”
Zanco, B., Mirth, C. K., Sgrò, C. M., & Piper, M. D. W. (2021) · eLife · doi:10.7554/elife.62335 · Cited by 85 · see citing works
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César, A. S. M., Regitano, L. C. D. A., Reecy, J. M., Poleti, M., de Oliveira, P. S. N., de Oliveira, G. B., Moreira, G. C. M., Mudadu, M. A., Tizioto, P. C., Koltes, J. E., et al. (2018) · BMC Genomics · doi:10.1186/s12864-018-4871-y · Cited by 84 · see citing works
Ng, M. Y. W., Charsou, C., Lapão, A., Singh, S., Trachsel-Moncho, L., Schultz, S. W., Nakken, S., Munson, M. J., & Simonsen, A. (2022) · Nature Communications · doi:10.1038/s41467-022-33933-2 · Cited by 89 · see citing works
Nakatsu, F., & Kawasaki, A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.664788 · Cited by 82 · see citing works
“This pool of cholesterol in the limiting membrane of lysosomes triggers the activation of mTORC1, the master regulator of growth, via Rag GTPases as well as the amino acid permease SLC38A9 (Castellano et al., 2017).”
BackgroundPI(3,4)P2 Signaling in Cancer and Metabolism
Gozzelino, L., Santis, M. C. D., Gulluni, F., Hirsch, E., & Martini, M. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00360 · Cited by 78 · see citing works
“Given that lysosomal cholesterol activates mTORC1 through solute carrier family 38 member 9 (75), it is evident that both the PI(3,4)P2 production by PI3K-C2β and the subsequent PI(3,4)P2-regulated cholesterol export from lysosomes contribute to the silencing of mTORC1.”
BackgroundArginine methylation is required for canonical Wnt signaling and endolysosomal trafficking
Albrecht, L. V., Ploper, D., Tejeda‐Muñoz, N., & Robertis, E. M. D. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1804091115 · Cited by 79 · see citing works
Fiorenza, M. T., Moro, E., & Erickson, R. P. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy155 · Cited by 77 · see citing works
Impairment of Lysosome Function and Autophagy in Rare Neurodegenerative Diseases
Darios, F. D., & Stévanin, G. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2020.02.033 · Cited by 77 · see citing works
The Architecture of the Rag GTPase Signaling Network
Nicastro, R., Sardu, A., Panchaud, N., & Virgilio, C. D. (2017) · Biomolecules · doi:10.3390/biom7030048 · Cited by 74 · see citing works
“In addition to glucose, cholesterol has also recently been found to activate the Rag GTPase-TORC1 branch via the arginine sensor/transporter SLC38A9, which binds lysosomal cholesterol through a conserved cholesterol-binding motif within its transmembrane helix 8 and mediates the respective signal in a manner that is i…”
BackgroundVanier, M. T., Platt, F. M., Eden, E. R., & Patterson, M. C. (2022) · doi:10.1002/9781119697312.ch14 · Cited by 76 · see citing works
The post‐translational regulation of transcription factor EB (TFEB) in health and disease
Takla, M., Keshri, S., & Rubinsztein, D. C. (2023) · EMBO Reports · doi:10.15252/embr.202357574 · Cited by 73 · see citing works
“Along with the cholesterol-and Arg-responsive lysosomal multipass trans-membrane protein, SLC38A9, possibly catalysing the formation of RagA GTP , this enables lysosomal recruitment of mTORC1 under conditions of amino acid and cholesterol sufficiency (Castellano et al , 2017; Shen & Sabatini, 2018).”
BackgroundmTOR signaling networks: mechanistic insights and translational frontiers in disease therapeutics
Zhang, H.-X., Xiao, X., Pan, Z.-R., & Dokudovskaya, S. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02493-4 · Cited by 90 · see citing works
“124 In contrast, the Niemann ‒ Pick C1 (NPC1) protein, which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function.”
Budelier, M. M., Cheng, W. W. L., Bergdoll, L. A., Chen, Z.-W., Janetka, J. W., Abramson, J., Krishnan, K., Mydock-McGrane, L. K., Covey, D. F., Whitelegge, J. P., et al. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.773069 · Cited by 73 · see citing works
“To determine cholesterol-binding sites in VDAC1, we photolabeled WT mouse VDAC1 (mVDAC1) with two cholesterol analogues that have a photoactive diazirine in either the 7-position (LKM38) (21) or the aliphatic tail (KK174) (see Fig.”
Method
- Authors
- Castellano, B. M., Thelen, A. M., Moldavski, O., Feltes, M., van der Welle, R. E. N., Mydock-McGrane, L., Jiang, X., van Eijkeren, R. J., Davis, O. B., Louie, S. M., Perera, R. M., Covey, D. F., Nomura, D. K., Ory, D. S., & Zoncu, R.
- Affiliations
- University of California, Berkeley (US)
- Washington University in St. Louis (US)
- Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.
- University of California, San Francisco (US)
- Corresponding author
- Castellano, Brian M.
- Thelen, Ashley M.
- Zoncu, Roberto
- ORCID
- Venue
- Science
- Published
- 2017-03-24
- Volume
- 355
- Issue
- 6331
- Pages
- 1306-1311
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5823611
- OpenAlex
- W2603916465
- Semantic Scholar
- 0cc6e6385fc09089703fcae595ecd7b42ea20c97
- Cited by
- 562
- References
- 36
- Citations by year
- 2026: 40 · 2025: 65 · 2024: 57 · 2023: 77 · 2022: 70 · 2021: 63 · 2020: 69 · 2019: 58 · 2018: 41 · 2017: 22
- FWCI
- 21.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (1DP2CA195761-01)
- Pew-Stewart Scholarship for Cancer Research
- Damon Runyon-Rachleff Innovation Award
- Edward Mallinckrodt, Jr. Foundation
- National Institutes of Health (R01 HL067773)
- Taylor Family Institute for Innovative Psychiatric Research
- National Science Foundation (DGE 1106400)
- Howard Hughes Medical Institute Gilliam Fellow
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- mTORC1, lysosomal cholesterol, SLC38A9, Niemann-Pick C1, lysosomes, sterol transport, nutrient signaling, growth regulation, arginine sensing, protein complexes
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Biological Transport, Carrier Proteins, Cholesterol, Cricetulus, Enzyme Activation, Fibroblasts, Humans, Cholesterol, HDL, Lysosomes, Mutation, Nuclear Proteins, Signal Transduction, CHO Cells, Amino Acid Motifs, Amino Acid Transport Systems, Multiprotein Complexes, Mice, HEK293 Cells, TOR Serine-Threonine Kinases
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