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

Jaiwei Xu; Haifang Zhao; Tao Wang

doi:10.1371/journal.pgen.1009172

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

PLoS Genet. 2020 Nov 2;16(11):e1009172. doi: 10.1371/journal.pgen.1009172. eCollection 2020 Nov.

Authors

Jaiwei Xu^{1

2}, Haifang Zhao², Tao Wang^{2

3}

Affiliations

¹ College of Biological Sciences, China Agricultural University, China.
² National Institute of Biological Sciences, China.
³ Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, China.

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 (Rh1G69D). We identified two novel E3 ubiquitin ligases SORDD1 and SORDD2 that effectively suppressed Rh1G69D-induced photoreceptor dysfunction and retinal degeneration. SORDD1/2 promoted the ubiquitination and degradation of Rh1G69D 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Genetically Modified
Disease Models, Animal
Drosophila Proteins / genetics
Drosophila Proteins / metabolism*
Drosophila melanogaster
Electroretinography
Endoplasmic Reticulum / metabolism
Endoplasmic Reticulum-Associated Degradation*
Gene Knockout Techniques
Humans
Larva
Microscopy, Electron, Scanning
Point Mutation
Proteasome Endopeptidase Complex / metabolism
Proteolysis
Retina / diagnostic imaging
Retina / pathology
Retina / ultrastructure
Retinitis Pigmentosa / diagnosis
Retinitis Pigmentosa / genetics
Retinitis Pigmentosa / pathology*
Rhodopsin / genetics
Rhodopsin / metabolism*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination
Valosin Containing Protein / metabolism

Substances

Drosophila Proteins
ninaE protein, Drosophila
Rhodopsin
Ubiquitin-Protein Ligases
Proteasome Endopeptidase Complex
Valosin Containing Protein
ter94 protein, Drosophila

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (81670891 and 81870693) awarded to T. Wang. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.