G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling
Copyright policy )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 (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.
- Newcastle University United Kingdom
- Heidelberg University Germany
- Freie Universität Berlin Germany
- KU Leuven Belgium
- Helmholtz Association of German Research Centres Germany
INTELLECTUAL DISABILITY, STRESS GRANULE FORMATION, Tuberous Sclerosis, Cell Movement, TUBEROUS SCLEROSIS, Insulin, GTPASE-ACTIVATING PROTEIN, Poly-ADP-Ribose Binding Proteins, VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical molecular biology: 711, mTORC1, Zebrafish, 11 Medical and Health Sciences, Neurons, RNA-Binding Proteins, Lysosomal Membrane Proteins, Phenotype, RNA Recognition Motif Proteins, lysosome, S6 KINASE, Female, MESSENGER-RNA, Life Sciences & Biomedicine, RNA Helicases, Signal Transduction, G3BP1, Biochemistry & Molecular Biology, G3BP2, EMC OR-01, 610, Breast Neoplasms, Mechanistic Target of Rapamycin Complex 1, stress granule, Cytoplasmic Granules, TSC complex, Article, Evolution, Molecular, 1300 Biochemistry, Genetics and Molecular Biology, Cell Line, Tumor, cancer, Animals, Humans, Amino Acid Sequence, Rats, Wistar, neuronal function, Adaptor Proteins, Signal Transducing, Science & Technology, 31 Biological sciences, DNA Helicases, Cell Biology, 32 Biomedical and clinical sciences, TSC1-TSC2 COMPLEX, 06 Biological Sciences, Rats, MAMMALIAN TARGET, Genomics England Research Consortium, CELL-GROWTH, RAPAMYCIN, Lysosomes, metabolism, VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk molekylærbiologi: 711, Developmental Biology
INTELLECTUAL DISABILITY, STRESS GRANULE FORMATION, Tuberous Sclerosis, Cell Movement, TUBEROUS SCLEROSIS, Insulin, GTPASE-ACTIVATING PROTEIN, Poly-ADP-Ribose Binding Proteins, VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical molecular biology: 711, mTORC1, Zebrafish, 11 Medical and Health Sciences, Neurons, RNA-Binding Proteins, Lysosomal Membrane Proteins, Phenotype, RNA Recognition Motif Proteins, lysosome, S6 KINASE, Female, MESSENGER-RNA, Life Sciences & Biomedicine, RNA Helicases, Signal Transduction, G3BP1, Biochemistry & Molecular Biology, G3BP2, EMC OR-01, 610, Breast Neoplasms, Mechanistic Target of Rapamycin Complex 1, stress granule, Cytoplasmic Granules, TSC complex, Article, Evolution, Molecular, 1300 Biochemistry, Genetics and Molecular Biology, Cell Line, Tumor, cancer, Animals, Humans, Amino Acid Sequence, Rats, Wistar, neuronal function, Adaptor Proteins, Signal Transducing, Science & Technology, 31 Biological sciences, DNA Helicases, Cell Biology, 32 Biomedical and clinical sciences, TSC1-TSC2 COMPLEX, 06 Biological Sciences, Rats, MAMMALIAN TARGET, Genomics England Research Consortium, CELL-GROWTH, RAPAMYCIN, Lysosomes, metabolism, VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk molekylærbiologi: 711, Developmental Biology
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