Schnyder corneal dystrophy-associated UBIAD1 inhibits ER-associated degradation of HMG CoA reductase in mice

Youngah Jo, Jason S. Hamilton, Seonghwan Hwang, Kristina Garland, Gennipher A. Smith, Shan Su, Iris Fuentes, Sudha Neelam, Bonne M. Thompson, Jeffrey G. McDonald, Russell A. Debose-Boyd

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere44396
JournaleLife
Volume8
DOIs
StatePublished - Feb 2019

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Jo, Y., Hamilton, J. S., Hwang, S., Garland, K., Smith, G. A., Su, S., Fuentes, I., Neelam, S., Thompson, B. M., McDonald, J. G., & Debose-Boyd, R. A. (2019). Schnyder corneal dystrophy-associated UBIAD1 inhibits ER-associated degradation of HMG CoA reductase in mice. eLife, 8, [e44396]. https://doi.org/10.7554/eLife.44396