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Autor(en) / Beteiligte

Titel

G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling

Ist Teil von

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek (Open access)

Beschreibungen/Notizen

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.

Sprache: Englisch
Identifikatoren: ISSN: 0092-8674, 1097-4172
eISSN: 1097-4172
DOI: 10.1016/j.cell.2020.12.024
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7868890

Format: –
Schlagworte: 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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