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RNF213 Acts as a Molecular Switch for Cav-1 Ubiquitination and Phosphorylation in Human Cells
Jungmi Choi1, Ryoichi Inoue1, Yuki Masuo1
1Laboratory of Molecular Biosciences, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Cells
|June 11, 2025
Summary
RNF213 protein regulates caveolin-1 (Cav-1) signaling by ubiquitination, impacting vascular health. This interaction is crucial for understanding Moyamoya disease and cellular responses to stress.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Genetics
Background:
- RNF213 protein possesses AAA+ ATPase and E3 ubiquitin ligase activities, implicated in vasculopathies like Moyamoya disease.
- The precise roles of RNF213 in human signaling pathways are not fully understood due to limited substrate identification.
- Caveolin-1 (Cav-1) is a key scaffolding protein regulating cellular processes and caveolae formation.
Purpose of the Study:
- To investigate the interaction between RNF213 and caveolin-1 (Cav-1).
- To elucidate the functional consequences of RNF213-Cav-1 interaction on cellular signaling and vascular health.
Main Methods:
- Investigated the binding interaction between RNF213 and Cav-1 using biochemical assays.
- Assessed the ubiquitination of Cav-1 by RNF213 in an ATP-dependent manner.
- Examined the effect of RNF213 on Cav-1 phosphorylation and nitric oxide bioavailability under oxidative stress.
Main Results:
- Cav-1 binds to the AAA+ domains of RNF213 in an ATP-dependent manner.
- RNF213 ubiquitinates Cav-1 via K48 and K63 linkages, with reduced polyubiquitination observed for Moyamoya disease-associated RNF213 mutations.
- RNF213 inhibits Cav-1 phosphorylation at Tyr14, affecting nitric oxide bioavailability in endothelial cells under oxidative stress.
Conclusions:
- RNF213 acts as a molecular switch modulating Cav-1 signaling based on its functionality and cellular conditions.
- The RNF213-Cav-1 axis provides new insights into vascular pathogenesis, particularly Moyamoya disease.
- Understanding this pathway is crucial for exploring novel therapeutic strategies for vascular disorders.
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