RRC ID 70311
Author Prentzell MT, Rehbein U, Cadena Sandoval M, De Meulemeester AS, Baumeister R, Brohée L, Berdel B, Bockwoldt M, Carroll B, Chowdhury SR, von Deimling A, Demetriades C, Figlia G, Genomics England Research Consortium, 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.
Title G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling.
Journal Cell
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.
Volume 184(3)
Pages 655-674.e27
Published 2021-2-4
DOI 10.1016/j.cell.2020.12.024
PII S0092-8674(20)31694-9
PMID 33497611
PMC PMC7868890
MeSH 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 Lysosome-Associated Membrane Glycoproteins / 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
IF 38.637
Zebrafish Tg(vglut2a:loxP-DsRed-loxP-GFP)