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.

视紫红质基因的突变是常染色体显性遗传性视网膜色素变性（adRP）的主要原因之一。视紫红质的突变形式经常累积在内质网（ER）中，引起ER应激，并触发感光细胞变性。在这里，我们进行了全基因组筛选，以鉴定^adRP果蝇模型中视网膜变性的抑制剂，该抑制剂在主要视紫红质Rh1（Rh1 ^G69D）中带有点突变。我们确定了两个新型的E3泛素连接酶SORDD1和SORDD2，它们可以有效抑制Rh1 ^G69D诱导的光感受器功能障碍和视网膜变性。SORDD1 / 2促进Rh1 ^G69D的泛素化和降解通过VCP（含缬草素的蛋白质）并且不依赖于HRD1（HMG-CoA还原酶降解蛋白1）/ HRD3复合物的过程。我们进一步证明，SORDD1 / 2和HRD1平行且以冗余方式起作用，以维持视紫红质的稳态和感光细胞的完整性。这些发现确定了一条新的ER相关蛋白降解（ERAD）途径，并表明促进SORDD1 / 2功能可能是治疗adRP的治疗策略。