PUBLICATION
G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling
- Authors
- Prentzell, M.T., Rehbein, U., Cadena Sandoval, M., De Meulemeester, A.S., Baumeister, R., Brohée, L., Berdel, B., Bockwoldt, M., Carroll, B., Chowdhury, S.R., von Deimling, A., Demetriades, C., Figlia, G., Genomics England Research Consortium, de Araujo, M.E.G., Heberle, A.M., Heiland, I., Holzwarth, B., Huber, L.A., Jaworski, J., Kedra, M., Kern, K., Kopach, A., Korolchuk, V.I., van 't Land-Kuper, I., Macias, M., Nellist, M., Palm, W., Pusch, S., Ramos Pittol, J.M., Reil, M., Reintjes, A., Reuter, F., Sampson, J.R., Scheldeman, C., Siekierska, A., Stefan, E., Teleman, A.A., Thomas, L.E., Torres-Quesada, O., Trump, S., West, H.D., de Witte, P., Woltering, S., Yordanov, T.E., Zmorzynska, J., Opitz, C.A., Thedieck, K.
- ID
- ZDB-PUB-210128-8
- Date
- 2021
- Source
- Cell 184(3): 655-674.e27 (Journal)
- Registered Authors
- Zmorzynska, Justyna
- Keywords
- G3BP1, G3BP2, TSC complex, cancer, lysosome, mTORC1, metabolism, neuronal function, stress granule
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/metabolism*
- Amino Acid Sequence
- Animals
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Cell Line, Tumor
- Cell Movement/drug effects
- Cytoplasmic Granules/drug effects
- Cytoplasmic Granules/metabolism
- DNA Helicases/chemistry
- DNA Helicases/metabolism*
- Evolution, Molecular
- Female
- Humans
- Insulin/pharmacology
- Lysosomal Membrane Proteins/metabolism
- Lysosomes/drug effects
- Lysosomes/metabolism*
- Mechanistic Target of Rapamycin Complex 1/metabolism*
- Neurons/drug effects
- Neurons/metabolism
- Phenotype
- Poly-ADP-Ribose Binding Proteins/chemistry
- Poly-ADP-Ribose Binding Proteins/metabolism*
- RNA Helicases/chemistry
- RNA Helicases/metabolism*
- RNA Recognition Motif Proteins/chemistry
- RNA Recognition Motif Proteins/metabolism*
- RNA-Binding Proteins/metabolism*
- Rats, Wistar
- Signal Transduction*/drug effects
- Tuberous Sclerosis/metabolism*
- Zebrafish/metabolism
- PubMed
- 33497611 Full text @ Cell
Citation
Prentzell, M.T., Rehbein, U., Cadena Sandoval, M., De Meulemeester, A.S., Baumeister, R., Brohée, L., Berdel, B., Bockwoldt, M., Carroll, B., Chowdhury, S.R., von Deimling, A., Demetriades, C., Figlia, G., Genomics England Research Consortium, de Araujo, M.E.G., Heberle, A.M., Heiland, I., Holzwarth, B., Huber, L.A., Jaworski, J., Kedra, M., Kern, K., Kopach, A., Korolchuk, V.I., van 't Land-Kuper, I., Macias, M., Nellist, M., Palm, W., Pusch, S., Ramos Pittol, J.M., Reil, M., Reintjes, A., Reuter, F., Sampson, J.R., Scheldeman, C., Siekierska, A., Stefan, E., Teleman, A.A., Thomas, L.E., Torres-Quesada, O., Trump, S., West, H.D., de Witte, P., Woltering, S., Yordanov, T.E., Zmorzynska, J., Opitz, C.A., Thedieck, K. (2021) G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling. Cell. 184(3):655-674.e27.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping