Schnyder corneal dystrophy-associated UBIAD1 inhibits ER-associated degradation of HMG CoA reductase in mice
| Autor: | Gennipher A Smith, Iris Fuentes, Seonghwan Hwang, Shan Su, Bonne M. Thompson, Jeffrey G. McDonald, Jason S. Hamilton, Kristina Garland, Youngah Jo, Sudha Neelam, Russell A. DeBose-Boyd |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Mouse Geranylgeranyl pyrophosphate Mutant Endoplasmic Reticulum ER-associated degradation vitamin K Pathogenesis Mice chemistry.chemical_compound 0302 clinical medicine geranylgeranyl pyrophosphate Biology (General) Corneal Dystrophies Hereditary 0303 health sciences biology General Neuroscience General Medicine Schnyder corneal dystrophy Cell biology HMG-CoA reductase Medicine Female lipids (amino acids peptides and proteins) QH301-705.5 Science Mice Transgenic macromolecular substances Endoplasmic-reticulum-associated protein degradation General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Biochemistry and Chemical Biology Animals 030304 developmental biology isoprenoid General Immunology and Microbiology Cholesterol Endoplasmic reticulum cholesterol Cell Biology Dimethylallyltranstransferase Sterol Mice Inbred C57BL chemistry Proteolysis biology.protein Hydroxymethylglutaryl CoA Reductases Research Advance 030217 neurology & neurosurgery |
| Zdroj: | eLife, Vol 8 (2019) eLife |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.44396 |
| Popis: | Autosomal-dominant Schnyder corneal dystrophy (SCD) is characterized by corneal opacification owing to overaccumulation of cholesterol. SCD is caused by mutations in UBIAD1, which utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize vitamin K2. Using cultured cells, we previously showed that sterols trigger binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase (HMGCR), thereby inhibiting its endoplasmic reticulum (ER)-associated degradation (ERAD) (Schumacher et al. 2015). GGpp triggers release of UBIAD1 from HMGCR, allowing maximal ERAD and ER-to-Golgi transport of UBIAD1. SCD-associated UBIAD1 resists GGpp-induced release and is sequestered in ER to inhibit ERAD. We now report knockin mice expressing SCD-associated UBIAD1 accumulate HMGCR in several tissues resulting from ER sequestration of mutant UBIAD1 and inhibition of HMGCR ERAD. Corneas from aged knockin mice exhibit signs of opacification and sterol overaccumulation. These results establish the physiological significance of UBIAD1 in cholesterol homeostasis and indicate inhibition of HMGCR ERAD contributes to SCD pathogenesis. |
| Databáze: | OpenAIRE |
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