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

Jaiwei Xu,Haifang Zhao,Tao Wang,Hyung Don Ryoo

doi:10.1371/journal.pgen.1009172

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.

Highlights

Misfolded membrane proteins, including G protein-coupled receptors (GPCRs), are often retained in the endoplasmic reticulum (ER) and an overabundance of ER-retained proteins is associated with many diseases
Misfolded rhodopsins accumulated in endoplasmic reticulum (ER) could disrupt the homeostasis of the ER and cause ER stress
We define novel ubiquitin E3 ligase SORDD1/2 based on a genetic screen and demonstrate that SORDD1/2 promotes the degradation of misfolded rhodopsins through ER-associated degradation (ERAD) pathway

Summary

Introduction

Misfolded membrane proteins, including G protein-coupled receptors (GPCRs), are often retained in the endoplasmic reticulum (ER) and an overabundance of ER-retained proteins is associated with many diseases. The Rho mutation most commonly associated with adRP is a proline to histidine mutation at position 23 (RhoP23H), which leads to Rho retention within the ER. This in turn leads to ER stress, activation of the unfolded protein response (UPR), and photoreceptor degeneration [2, 5,6,7,8]. This is seen in both human patients and animal models of the disease

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Conclusion