G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling

Prentzell MT, Rehbein U, Cadena Sandoval M, De Meulemeester AS, Baumeister R, Carroll B, Demetriades C, Korolchuk VI, Nellist M, Palm W, Sampson JR, Teleman AA · 2021 · Cell · Atlas ID PRE2021

What this study shows

Adds a physical brake upstream of mTORC1. G3BP1 and G3BP2, known until then as core stress-granule proteins, also sit on the cytoplasmic face of the lysosome and are what holds the TSC complex there; without them TSC cannot reach its target and mTORC1 becomes over-responsive to amino acids and insulin. Loss of G3BP1 reproduces TSC-like hyperactivity phenotypes: faster mTORC1-driven motility in breast cancer cells, with low G3BP1 correlating with worse patient outcome, and disturbed neuronal development in zebrafish. Relevant to the Atlas because it is a lysosomal tethering step that the canonical Rheb/TSC diagram does not show.

Abstract

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Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity.

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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 and mouse cells; breast cancer patient data; zebrafish) 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 and mouse cells; breast cancer patient data; zebrafish
Journal	Cell
Year	2021
Peer reviewed	Yes
Record last updated	2026-09-23
Source	DOI 10.1016/j.cell.2020.12.024 · PMID 33497611

Cite this paper

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Prentzell, M. T., Rehbein, U., Cadena Sandoval, M., De Meulemeester, A. S., Baumeister, R., Carroll, B., Demetriades, C., Korolchuk, V. I., Nellist, M., Palm, W., Sampson, J. R., Teleman, A. A., Opitz, C. A., & Thedieck, K. (2021). G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling. Cell. https://doi.org/10.1016/j.cell.2020.12.024

@article{PRE2021,
  author       = {Prentzell, M. T. and Rehbein, U. and Cadena Sandoval, M. and De Meulemeester, A. S. and Baumeister, R. and Carroll, B. and Demetriades, C. and Korolchuk, V. I. and Nellist, M. and Palm, W. and Sampson, J. R. and Teleman, A. A. and Opitz, C. A. and Thedieck, K.},
  title        = {{G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling}},
  journal      = {Cell},
  year         = {2021},
  doi          = {10.1016/j.cell.2020.12.024},
  note         = {PMID: 33497611},
}

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 PRE2021) [Data set]. https://mtor-atlas.org/study/PRE2021/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_PRE2021,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record PRE2021},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/PRE2021/},
  doi          = {10.5281/zenodo.22059963}
}