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G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling

Prentzell, Mirja Tamara, Rehbein, Ulrike, Cadena Sandoval, Marti, De Meulemeester, Ann-Sofie, Baumeister, Ralf, Brohée, Laura, Berdel, Bianca, Bockwoldt, Mathias, Carroll, Bernadette, Chowdhury, Suvagata Roy, von Deimling, Andreas, Demetriades, Constantinos, Figlia, Gianluca, de Araujo, Mariana Eca Guimaraes, Heberle, Alexander M., Heiland, Ines, Holzwarth, Birgit, Huber, Lukas A., Jaworski, Jacek, Kedra, Magdalena, Kern, Katharina, Kopach, Andrii, Korolchuk, Viktor I., van 't Land-Kuper, Ineke, Macias, Matylda, Nellist, Mark, Palm, Wilhelm, Pusch, Stefan, Ramos Pittol, Jose Miguel, Reil, Michèle, Reintjes, Anja, Reuter, Friederike, Sampson, Julian R., Scheldeman, Chloë, Siekierska, Aleksandra, Stefan, Eduard, Teleman, Aurelio A., Thomas, Laura E., Torres-Quesada, Omar, Trump, Saskia, West, Hannah D., de Witte, Peter, Woltering, Sandra, Yordanov, Teodor E., Zmorzynska, Justyna, Opitz, Christiane A. and Thedieck, Kathrin 2021. G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling. Cell 184 (3) , P655-674.E27. 10.1016/j.cell.2020.12.024

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Publisher: Elsevier
ISSN: 0092-8674
Date of First Compliant Deposit: 3 March 2021
Date of Acceptance: 14 December 2020
Last Modified: 04 Mar 2021 11:00
URI: https://orca.cardiff.ac.uk/id/eprint/139248

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