The DOI matches its Crossref record; 36 of the 36 references it cites were found in a registry or an index.
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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In the citing paper
“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]
In the citing paper
“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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The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1
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Self-citationActivation of a metabolic gene regulatory network downstream of mTOR complex 1
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Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity
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Self-citation[19] Receptor-mediated endocytosis of low-density lipoprotein in cultured cells
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Protein Sensors for Membrane Sterols
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Regulation of TORC1 by Rag GTPases in nutrient response
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A Century of Cholesterol and Coronaries: From Plaques to Genes to Statins
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Sorted by citations
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Liu, G. Y., & Sabatini, D. M. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0199-y · Cited by 2,737
Lysosomes as dynamic regulators of cell and organismal homeostasis
Ballabio, A., & Bonifacino, J. S. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0185-4 · Cited by 1,469
mTOR signalling and cellular metabolism are mutual determinants in cancer
Mossmann, D., Park, S., & Hall, M. N. (2018) · Nature reviews. Cancer · doi:10.1038/s41568-018-0074-8 · Cited by 1,088
The lysosome as a cellular centre for signalling, metabolism and quality control
Lawrence, R. E., & Zoncu, R. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0244-7 · Cited by 920
Self-citationTargeting mTOR for cancer therapy
Hua, H. M., Kong, Q., Zhang, H., Wang, J., Luo, T. L., & Jiang, Y. (2019) · Journal of Hematology & Oncology · doi:10.1186/s13045-019-0754-1 · Cited by 929
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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