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

Autoři: Jaiwei Xu aff001;  Haifang Zhao aff002;  Tao Wang aff002
Působiště autorů: College of Biological Sciences, China Agricultural University, China aff001;  National Institute of Biological Sciences, China aff002;  Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, China aff003
Vyšlo v časopise: Suppression of retinal degeneration by two novel ERAD ubiquitin E3 ligases SORDD1/2 in Drosophila. PLoS Genet 16(11): e32767. doi:10.1371/journal.pgen.1009172
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009172


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.

Klíčová slova:

Endoplasmic reticulum – Eyes – Homeostasis – Ligases – Photoreceptors – Proteasomes – Retinal degeneration – Ubiquitin ligases


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