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Prentzell, M.T. (Mirja Tamara), Rehbein, U. (Ulrike), Cadena Sandoval, M. (Marti), De Meulemeester, A.-S. (Ann-Sofie), Baumeister, R. (Ralf), Brohée, L. (Laura), Berdel, B. (Bianca), Bockwoldt, M. (Mathias), Carroll, B. (Bernadette), Chowdhury, S.R. (Suvagata Roy), et al. A. von Deimling (Andreas), Demetriades, C. (Constantinos), Figlia, G. (Gianluca), de Araujo, M.E.G. (Mariana Eca Guimaraes), Heberle, A.M. (Alexander M.), Heiland, I. (Ines), Holzwarth, B. (Birgit), Huber, L.A. (Lukas A.), Jaworski, J. (Jacek), Kedra, M. (Magdalena), Kern, K. (Katharina), Kopach, A. (Andrii), Korolchuk, V.I. (Viktor I.), van 't Land-Kuper, I. (Ineke), Macias, M. (Matylda), M.D. Nellist (Mark), Palm, W. (Wilhelm), Pusch, S. (Stefan), Ramos Pittol, J.M. (Jose Miguel), Reil, M. (Michèle), Reintjes, A. (Anja), Reuter, F. (Friederike), Sampson, J.R. (Julian R.), Scheldeman, C. (Chloë), Siekierska, A. (Aleksandra), Stefan, E. (Eduard), Teleman, A.A. (Aurelio A.), Thomas, L.E. (Laura E.), Torres-Quesada, O. (Omar), Trump, S. (Saskia), West, H.D. (Hannah D.), de Witte, P. (Peter), Woltering, S. (Sandra), Yordanov, T.E. (Teodor E.), Zmorzynska, J. (Justyna), Opitz, C.A. (Christiane A.) and Thedieck, K. (Kathrin)

2021-02-04

G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling

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Publication

Cell , Volume 184 - Issue 3 p. 655- 674.e27

Distinct from their contributions to stress granules, G3BPs regulate mTORC1 activity through spatial control of the TSC complex.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. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling.

Additional Metadata
Keywords cancer, G3BP1, G3BP2, lysosome, metabolism, mTORC1, neuronal function, stress granule, TSC complex
Persistent URL doi.org/10.1016/j.cell.2020.12.024, hdl.handle.net/1765/134603
Journal Cell
Organisation Department of Clinical Genetics
Citation
Prentzell, M.T. (Mirja Tamara), Rehbein, U. (Ulrike), Cadena Sandoval, M. (Marti), De Meulemeester, A.-S. (Ann-Sofie), Baumeister, R. (Ralf), Brohée, L. (Laura), … Thedieck, K. (Kathrin). (2021). G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling. Cell, 184(3), 655–674.e27. doi:10.1016/j.cell.2020.12.024
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