Suppression of retinal degeneration by two novel ERAD ubiquitin E3 ligases SORDD1/2 in Drosophila

Abstract

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.

PERK prevents rhodopsin degradation during retinitis pigmentosa by inhibiting IRE1-induced autophagy

“…These data suggest that the UPS system is impaired when PERK is blocked during ER stress. Moreover, expression of the E3 ligase SORDD1 ( Xu et al, 2020 ) in Rh1 P37H -GFP perk RNAi photoreceptor cells prevented the accumulated Rh1 P37H -GFP ( Fig. 7, E and F ) but did not affect wild-type Rh1 levels.…”

“…1 D ; Galy et al, 2005 ). Moreover, Rh1 P37H -GFP induced ER stress, as both ATF4-mCherry and XBP1-mCherry (two independent reporters of ER stress) were expressed and activated in Rh1 P37H -GFP retinas, but not in retinas expressing wild-type Rh1-GFP ( Kang and Ryoo, 2009 ; Xu et al, 2020 ; Fig. 1, E–H ).…”

ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model

“…Our model is further supported by the findings that E3 ubiquitin ligases, SORDD1/2, was able to facilitate degradation of Rh1 P37H (the Drosophila equivalent of P23H rhodopsin) at larval and earlier stages of growth to allow for development of healthy adult eyes. Furthermore, SORDD1/2 and HRD1/ SYVN1 were also able to prevent retinal degeneration in Drosophila with the G69D (glycine to aspartic acid at amino acid residue 69) rhodopsin mutation 52 . The lack of Atf6 in Rho +/P23H mice may initially increase the ability of E3 ubiquitin ligases downstream of IRE1-XBP-1s-ERAD to target misfolded rhodopsin in early stages of life.…”

Untitled

“…Flies bearing one copy of the ninaE G69D allele have total Rh1 protein levels reduced by more than half, indicating that both the mutant and the wild type Rhodopsin-1 proteins undergo degradation in these flies [9,10]. Three ubiquitin ligases that specialize in the degradation of misfolded endoplasmic reticulum (ER) proteins mediate the degradation of Rh1 in ninaE G69D flies [16]. Overexpression of these ubiquitin ligases can delay the onset of retinal degeneration in Drosophila ninaE G69D flies, suggesting that excessive ER stress imposed by mutant Rh1 is a contributing factor to retinal degeneration [14,16].…”

“…Three ubiquitin ligases that specialize in the degradation of misfolded endoplasmic reticulum (ER) proteins mediate the degradation of Rh1 in ninaE G69D flies [16]. Overexpression of these ubiquitin ligases can delay the onset of retinal degeneration in Drosophila ninaE G69D flies, suggesting that excessive ER stress imposed by mutant Rh1 is a contributing factor to retinal degeneration [14,16].…”