2. Academic Validation
  3. Retinitis pigmentosa 2 pathogenic mutants degrade through BAG6/HUWE1 complex

Retinitis pigmentosa 2 pathogenic mutants degrade through BAG6/HUWE1 complex

  • Exp Eye Res. 2022 Jul;220:109110. doi: 10.1016/j.exer.2022.109110.
Jing Zhang 1,  Hongying Gao 1,  Ning Jiang 1,  Min Jing 1,  Ziwei Sun 1,  Chunxiao Du 1,  Jun Zhang 1,  Mingli Wang 1,  Jing Li 1,  Fen Gao 2,  Yanzhong Hu 3,  Hongmei Mu 4,  Xiukun Cui 5
Affiliations

Affiliations

  • 1 Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Medicine, Henan University, Kaifeng, China.
  • 2 Kaifeng Key Lab of Myopia and Cataract, Kaifeng Central Hospital, Kaifeng, China.
  • 3 Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Medicine, Henan University, Kaifeng, China; Department of Ophthalmology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address: hyz@henu.edu.cn.
  • 4 Kaifeng Key Lab of Myopia and Cataract, Kaifeng Central Hospital, Kaifeng, China. Electronic address: muhongmeik@126.com.
  • 5 Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, School of Medicine, Henan University, Kaifeng, China. Electronic address: xkcui@henu.edu.cn.
PMID: 35569519 DOI: 10.1016/j.exer.2022.109110
Abstract

Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease which is the major cause of vision loss. X-linked RP patients account for 5%-15% of all inherited RP cases and mutations in RP2 (Retinitis pigmentosa 2) were responsible for about 20% X-linked RP families. A majority of RP2 pathogenic mutations displayed a vulnerable protein stability and degraded rapidly through ubiquitin-proteasome system (UPS). Though the RP2 protein could be readily recovered by Proteasome inhibitors, e.g., MG132, their applications for RP2-related RP therapy were limited by their nonspecific characterization. In the present study, we aimed to identify UPS-related factors, such as E3 Ligases, which are specifically involved in degradation of RP2 pathogenic mutants. We identified several E3 Ligases, such as HUWE1, and the co-chaperon BAG6 specifically interacting with RP2 pathogenic mutants. Knockdown of HUWE1 and BAG6 could partially rescue the reduced protein levels of RP2 mutants. BAG6 is required for recruitment of HUWE1 to ubiquitinate RP2 mutants at the K268 site. The HUWE1 inhibitor BI8622 could restore the levels of RP2 mutant and then the binding to its partner ARL3 in retina cell lines. This study revealed the details of UPS-related degradation of RP2 mutants and possibly provided a potential treatment for RP2-related RP.

Keywords

BAG6; BI8622; Degradation; HUWE1; RP2; Retinitis pigmentosa.

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