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G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling

Lookup NU author(s): Marti Cadena Sandoval, Dr Bernadette Carroll, Professor Viktor KorolchukORCiD

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Abstract

© 2021 The AuthorsDistinct from their contributions to stress granules, G3BPs regulate mTORC1 activity through spatial control of the TSC complex.© 2021 The AuthorsRas 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.

Publication metadata

Author(s): Prentzell MT, Rehbein U, Cadena Sandoval M, De Meulemeester A-S, Baumeister R, Brohee L, Berdel B, Bockwoldt M, Carroll B, Chowdhury SR, von Deimling A, Demetriades C, Figlia G, de Araujo MEG, Heberle AM, Heiland I, Holzwarth B, Huber LA, Jaworski J, Kedra M, Kern K, Kopach A, Korolchuk VI, van 't Land-Kuper I, Macias M, Nellist M, Palm W, Pusch S, Ramos Pittol JM, Reil M, Reintjes A, Reuter F, Sampson JR, Scheldeman C, Siekierska A, Stefan E, Teleman AA, Thomas LE, Torres-Quesada O, Trump S, West HD, de Witte P, Woltering S, Yordanov TE, Zmorzynska J, Opitz CA, Thedieck K

Publication type: Article

Publication status: Published

Journal: Cell

Year: 2021

Volume: 184

Issue: 3

Pages: 655-674.e27

Print publication date: 04/02/2021

Online publication date: 25/01/2021

Acceptance date: 14/12/2020

Date deposited: 01/04/2021

ISSN (print): 0092-8674

ISSN (electronic): 1097-4172

Publisher: Elsevier B.V.

URL: https://doi.org/10.1016/j.cell.2020.12.024

DOI: 10.1016/j.cell.2020.12.024

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