G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling

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 (...

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Published in:Cell 2021-02, Vol.184 (3), p.655-674.e27
Main Authors: 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., Thedieck, Kathrin
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Amino Acid Sequence
Animals
Basale medisinske, odontologiske og veterinærmedisinske fag: 710
Basic medical, dental and veterinary science disciplines: 710
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
cancer
Cell Line, Tumor
Cell Movement - drug effects
Cytoplasmic Granules - drug effects
Cytoplasmic Granules - metabolism
DNA Helicases - chemistry
DNA Helicases - metabolism
Evolution, Molecular
Female
G3BP1
G3BP2
Humans
Insulin - pharmacology
Lysosomal Membrane Proteins - metabolism
lysosome
Lysosomes - drug effects
Lysosomes - metabolism
Mechanistic Target of Rapamycin Complex 1 - metabolism
Medical disciplines: 700
Medical molecular biology: 711
Medisinsk molekylærbiologi: 711
Medisinske Fag: 700
metabolism
mTORC1
neuronal function
Neurons - drug effects
Neurons - metabolism
Phenotype
Poly-ADP-Ribose Binding Proteins - chemistry
Poly-ADP-Ribose Binding Proteins - metabolism
Rats
Rats, Wistar
RNA Helicases - chemistry
RNA Helicases - metabolism
RNA Recognition Motif Proteins - chemistry
RNA Recognition Motif Proteins - metabolism
RNA-Binding Proteins - metabolism
Signal Transduction - drug effects
stress granule
TSC complex
Tuberous Sclerosis - metabolism
VDP
Zebrafish - metabolism
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Summary: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. [Display omitted] •G3BPs act non-redundantly in the TSC-mTORC1 signaling axis•G3BPs reside at the lysosomal surface and inhibit mTORC1•The TSC complex requires G3BPs as its lysosomal tether•G3BP1 deficiency phenocopies TSC complex loss in cancer cells and neurons Distinct from their contributions to stress granules, G3BPs regulate mTORC1 activity through spatial control of the TSC complex.
ISSN:0092-8674
1097-4172
1097-4172
DOI:10.1016/j.cell.2020.12.024