生物
视网膜变性
视紫红质
内质网相关蛋白降解
泛素
细胞生物学
内质网
色素性视网膜炎
泛素连接酶
黑腹果蝇
未折叠蛋白反应
突变体
遗传学
视网膜
生物化学
基因
作者
Jaiwei Xu,Haifang Zhao,Tao Wang
出处
期刊:PLOS Genetics
日期:2020-11-02
卷期号:16 (11): e1009172-e1009172
被引量:8
标识
DOI:10.1371/journal.pgen.1009172
摘要
Mutations in the gene rhodopsin are one of the major causes of autosomal dominant retinitis pigmentosa (adRP). Mutant forms of Rhodopsin frequently accumulate in the endoplasmic reticulum (ER), cause ER stress, and trigger photoreceptor cell degeneration. Here, we performed a genome-wide screen to identify suppressors of retinal degeneration in a Drosophila model of adRP, carrying a point mutation in the major rhodopsin, Rh1 (Rh1 G69D ). We identified two novel E3 ubiquitin ligases SORDD1 and SORDD2 that effectively suppressed Rh1 G69D -induced photoreceptor dysfunction and retinal degeneration. SORDD1/2 promoted the ubiquitination and degradation of Rh1 G69D through VCP (valosin containing protein) and independent of processes reliant on the HRD1 (HMG-CoA reductase degradation protein 1)/HRD3 complex. We further demonstrate that SORDD1/2 and HRD1 function in parallel and in a redundant fashion to maintain rhodopsin homeostasis and integrity of photoreceptor cells. These findings identify a new ER-associated protein degradation (ERAD) pathway and suggest that facilitating SORDD1/2 function may be a therapeutic strategy to treat adRP.
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