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Fluorescence Recovery after Photobleaching of Yellow Fluorescent Protein Tagged p62 in Aggresome-like Induced Structures
Published on: March 26, 2019
G3BP1 inhibits ubiquitinated protein aggregations induced by p62 and USP10
Sergei Anisimov1, Masahiko Takahashi1, Taichi Kakihana1
1Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan.
Abstract:
The aberrant accumulation of ubiquitinated protein aggregates in cells plays a critical role in the pathogenesis of several degenerative diseases, including Parkinson disease (PD) and cystic fibrosis (CF). In this study, we found that Ras GTPase-activating protein-binding protein 1 (G3BP1) inhibits ubiquitinated protein aggregations induced by p62 and USP10 in cultured cells. p62 is a ubiquitin receptor, and p62 and its binding partner USP10 have been shown to augment ubiquitinated protein aggregation. G3BP1 interacted with p62 and USP10 and inhibited p62/USP10-induced protein aggregation. The G3BP1 inhibition of protein aggregations targeted two aggregation-prone proteins, α-synuclein and CFTR-ΔF508, which are causative factors of PD and CF, respectively. G3BP1 depletion increased the amounts of ubiquitinated α-synuclein and CFTR-ΔF508 protein. A proteasome reporter indicated that G3BP1 depletion inhibits the proteasome activity. We herein present evidence that G3BP1, p62 and USP10 together control ubiquitinated protein toxicity by controlling both ubiquitination and aggregation. Taken together, these results suggest that G3BP1, p62 and USP10 could be therapeutic targets for ubiquitinated protein aggregation disorders, including PD and CF.
Insights
Ras GTPase-activating protein-binding protein 1 (G3BP1) inhibits toxic protein aggregation in Parkinson disease and cystic fibrosis models. G3BP1, p62, and USP10 regulate ubiquitinated protein toxicity, suggesting therapeutic potential.
Area of Science:
- Cell Biology
- Neurodegenerative Diseases
- Genetic Disorders
Background:
- Aberrant accumulation of ubiquitinated protein aggregates is central to diseases like Parkinson disease (PD) and cystic fibrosis (CF).
- p62, a ubiquitin receptor, and its partner USP10 promote ubiquitinated protein aggregation.
- α-synuclein and CFTR-ΔF508 are aggregation-prone proteins linked to PD and CF, respectively.
Purpose of the Study:
- To investigate the role of Ras GTPase-activating protein-binding protein 1 (G3BP1) in regulating ubiquitinated protein aggregation.
- To determine if G3BP1 affects the aggregation of α-synuclein and CFTR-ΔF508.
- To explore the potential of G3BP1, p62, and USP10 as therapeutic targets.
Main Methods:
- Cell culture experiments to study protein aggregation.
- Co-immunoprecipitation to assess protein interactions.
- Proteasome activity assays using a reporter system.
Main Results:
- G3BP1 was found to inhibit p62/USP10-induced ubiquitinated protein aggregation.
- G3BP1 interacted with p62 and USP10, reducing aggregation of α-synuclein and CFTR-ΔF508.
- G3BP1 depletion impaired proteasome activity and increased aggregation of disease-associated proteins.
Conclusions:
- G3BP1, p62, and USP10 collectively regulate ubiquitinated protein toxicity by controlling ubiquitination and aggregation.
- These proteins represent potential therapeutic targets for disorders characterized by ubiquitinated protein aggregation, such as PD and CF.
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