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Retinitis pigmentosa 2 pathogenic mutants degrade through BAG6/HUWE1 complex
Jing Zhang1, Hongying Gao1, Ning Jiang1
1Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Medicine, Henan University, Kaifeng, China.
Experimental Eye Research
|May 15, 2022
Summary
Researchers identified specific factors, HUWE1 and BAG6, that degrade RP2 protein mutants in X-linked retinitis pigmentosa (RP). Inhibiting these factors may offer a targeted therapy for vision loss caused by RP2 mutations.
Area of Science:
- Genetics
- Molecular Biology
- Ophthalmology
Background:
- Retinitis pigmentosa (RP) is a leading cause of inherited vision loss.
- X-linked RP accounts for 5-15% of RP cases, with RP2 mutations in ~20% of families.
- Pathogenic RP2 mutants are unstable and rapidly degraded by the ubiquitin-proteasome system (UPS).
Purpose of the Study:
- To identify specific UPS-related factors, like E3 ligases, involved in RP2 mutant degradation.
- To explore potential therapeutic targets for RP2-related inherited retinal disease.
Main Methods:
- Investigated interactions between RP2 mutants and E3 ligases.
- Utilized knockdown of candidate E3 ligases (HUWE1, BAG6).
- Employed an E3 ligase inhibitor (BI8622) to assess RP2 protein restoration.
Main Results:
- Identified HUWE1 and BAG6 as key factors interacting with RP2 pathogenic mutants.
- Knockdown of HUWE1 or BAG6 partially restored RP2 mutant protein levels.
- BAG6 facilitates HUWE1 recruitment for RP2 ubiquitination at K268.
- HUWE1 inhibition restored RP2 mutant levels and ARL3 binding in retinal cells.
Conclusions:
- Elucidated the UPS-mediated degradation pathway for RP2 mutants.
- Identified HUWE1 and BAG6 as potential therapeutic targets for RP2-related RP.
- Suggests E3 ligase inhibition as a viable strategy for treating specific forms of inherited retinal degeneration.
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