Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex

Castellano BM, Thelen AM, Moldavski O, Feltes M, van der Welle REN, Mydock-McGrane L, Jiang X, van Eijkeren RJ, Davis OB, Louie SM, Perera RM, …, Zoncu R · 2017 · Science · Atlas ID CAS2017

What this study shows

Establishes lysosomal cholesterol as a nutrient input that drives mTORC1 recruitment and activation at the lysosomal surface. SLC38A9 is required for cholesterol-driven mTORC1 activation through conserved cholesterol-responsive motifs, and does so independently of its arginine-sensing function; NPC1, which exports cholesterol from the lysosome, binds SLC38A9 and restrains mTORC1 through its sterol transport function. Boundary: cell lines and patient-derived fibroblasts, no organismal endpoint.

Abstract

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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.

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At a glance

Evidence type	M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Human cell lines (HEK293T), CHO cells, NPC patient fibroblasts) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
Study type	5 - Mechanistic / In Vitro
Model system	Human cell lines (HEK293T), CHO cells, NPC patient fibroblasts
Journal	Science
Year	2017
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1126/science.aag1417 · PMID 28336668 · Free full text (PMC5823611)

In the Atlas

Cite this paper

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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. (2017). Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex. Science. https://doi.org/10.1126/science.aag1417

@article{CAS2017,
  author       = {Castellano, B. M. and Thelen, A. M. and Moldavski, O. and Feltes, M. and van der Welle, R. E. N. and Mydock-McGrane, L. and Jiang, X. and van Eijkeren, R. J. and Davis, O. B. and Louie, S. M. and Perera, R. M. and Covey, D. F. and Nomura, D. K. and Ory, D. S. and Zoncu, R.},
  title        = {{Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex}},
  journal      = {Science},
  year         = {2017},
  doi          = {10.1126/science.aag1417},
  note         = {PMID: 28336668},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record CAS2017) [Data set]. https://mtor-atlas.org/study/CAS2017/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_CAS2017,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record CAS2017},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/CAS2017/},
  doi          = {10.5281/zenodo.22059963}
}

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