Retinitis pigmentosa 2 pathogenic mutants degrade through BAG6/HUWE1 complex
Retinitis pigmentosa 2 pathogenic mutants degrade through BAG6/HUWE1 complex
复制标题
色素性视网膜炎 2 致病突变体通过 BAG6/HUWE1 复合物降解
DOI：
10.1016/j.exer.2022.109110
复制
发表时间：
2022
影响因子：
3.4
通讯作者：
Xiukun Cui
中科院分区：
文献类型：
--
作者：
Jing Zhang;Hongying Gao;Ning Jiang;Min Jing;Ziwei Sun;Chunxiao Du;Jun Zhang;Mingli Wang;Jing Li;Fen Gao;Yanzhong Hu;Hongmei Mu;Xiukun Cui
视网膜色素变性（RP）是最常见的遗传性视网膜变性疾病，是视力下降的主要原因。X连锁RP患者占所有遗传性RP病例的5%-15%，约20%的X连锁RP家族是由RP 2（Retinitispigmentosa 2）突变引起的。大多数RP 2致病突变显示出脆弱的蛋白质稳定性，并通过泛素-蛋白酶体系统（UPS）迅速降解。尽管RP 2蛋白可以容易地通过蛋白酶体抑制剂回收，例如，MG 132，它们的应用RP 2相关的RP治疗的限制，他们的非特异性表征。在本研究中，我们的目的是确定UPS相关的因素，如E3连接酶，这是专门参与降解RP 2致病突变体。我们鉴定了几种E3连接酶，如HUWE 1，以及与RP 2致病突变体特异性相互作用的辅伴侣BAG 6。HUWE 1和BAG 6的敲除可以部分地挽救RP 2突变体的蛋白水平降低。BAG 6是HUWE 1在K268位点泛素化RP 2突变体所必需的。HUWE 1抑制剂BI 8622可以恢复视网膜细胞系中RP 2突变体的水平，然后恢复与其伴侣ARL 3的结合。这项研究揭示了RP 2突变体的UPS相关降解的细节，并可能为RP 2相关RP提供潜在的治疗。
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.