Article ; Online: G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling.
2021 Volume 184, Issue 3, Page(s) 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 ... ...
| 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. |
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| MeSH term(s) | 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 ; Rats | ||||||||||
| Chemical Substances | Adaptor Proteins, Signal Transducing ; G3BP2 protein, human ; Insulin ; Lysosomal Membrane Proteins ; Poly-ADP-Ribose Binding Proteins ; RNA Recognition Motif Proteins ; RNA-Binding Proteins ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; DNA Helicases (EC 3.6.4.-) ; G3BP1 protein, human (EC 3.6.4.12) ; RNA Helicases (EC 3.6.4.13) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2021-01-25 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | ||||||||||
| ZDB-ID | 187009-9 | ||||||||||
| ISSN | 1097-4172 ; 0092-8674 | ||||||||||
| ISSN (online) | 1097-4172 | ||||||||||
| ISSN | 0092-8674 | ||||||||||
| DOI | 10.1016/j.cell.2020.12.024 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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