Open AccessSuppression of retinal degeneration by two novel ERAD ubiquitin E3 ligases SORDD1/2 in Drosophila
Author(s) -
Jaiwei Xu,
Haifang Zhao,
Tao Wang
Publication year - 2020
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1009172
Subject(s) - biology , retinal degeneration , rhodopsin , endoplasmic reticulum associated protein degradation , ubiquitin , microbiology and biotechnology , endoplasmic reticulum , retinitis pigmentosa , ubiquitin ligase , drosophila melanogaster , unfolded protein response , mutant , genetics , retinal , biochemistry , gene
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.