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Lysosomal cholesterol activates mTORC1 via an SLC38A9–Niemann-Pick C1 signaling complex
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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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“mTORC1 is regulated by a wide range of nutrients and hormonal cues, most notably the availability of amino acids, but also glucose, oxygen, and cholesterol 1–3.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [1]
Experimental — accuracy not yet measuredIn the citing paper
“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]
In the citing paper
“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]
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“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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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
Regulation of mTORC1 by Upstream Stimuli
Melick, C. H., & Jewell, J. L. (2020) · Genes · doi:10.3390/genes11090989 · Cited by 104
“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
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
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 95
“[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 98
Liu, F., Tian, T., Zhang, Z., Xie, S., Yang, J., Zhu, L., Wang, W., Shi, C., Sang, L., Guo, K., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00616-7 · Cited by 97
Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex
Su, M.-Y., Morris, K. L., Kim, D. J., Fu, Y., Lawrence, R. E., Stjepanović, G., Zoncu, R., & Hurley, J. H. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.10.016 · Cited by 96
“…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 99
“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 98
“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 88
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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 87
Ng, M. Y. W., Charsou, C., Lapao, 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 59
Nakatsu, F., & Kawasaki, A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.664788 · Cited by 78
“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 79
“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
Fiorenza, M. T., Moro, E., & Erickson, R. P. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy155 · Cited by 77
Impairment of Lysosome Function and Autophagy in Rare Neurodegenerative Diseases
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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 76
“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) · Wiley eBooks · doi:10.1002/9781119697312.ch14 · Cited by 79
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 77
“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., Xiao, X., Pan, Z., & Dokudovskaya, S. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02493-4 · Cited by 94
“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 77
“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
Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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