1. Biochemistry and Chemical Biology
  2. Cell Biology

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

  1. Youngah Jo
  2. Jason S Hamilton
  3. Seonghwan Hwang
  4. Kristina Garland
  5. Gennipher A Smith
  6. Shan Su
  7. Iris Fuentes
  8. Sudha Neelam
  9. Bonne M Thompson
  10. Jeffrey G McDonald
  11. Russell A DeBose-Boyd  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
https://doi.org/10.7554/eLife.44396
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Cite this article
  1. Youngah Jo
  2. Jason S Hamilton
  3. Seonghwan Hwang
  4. Kristina Garland
  5. Gennipher A Smith
  6. Shan Su
  7. Iris Fuentes
  8. Sudha Neelam
  9. Bonne M Thompson
  10. Jeffrey G McDonald
  11. Russell A DeBose-Boyd
(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
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  3. Download .RIS

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.

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All data generated in this study are included in the manuscript.

Article and author information

Author details

  1. Youngah Jo

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Jason S Hamilton

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3291-3125

  3. Seonghwan Hwang

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Kristina Garland

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Gennipher A Smith

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Shan Su

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9369-1642

  7. Iris Fuentes

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Sudha Neelam

    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Bonne M Thompson

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Jeffrey G McDonald

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Russell A DeBose-Boyd

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    Russell.Debose-Boyd@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7452-5227

Funding

National Institutes of Health (HL-20948)

  • Russell A DeBose-Boyd

National Institutes of Health (GM-112409)

  • Russell A DeBose-Boyd

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for Care and Use of Laboratory Animals of the National Institutes of Health. All of the animal work described in this manuscript has been approved and conducted under the oversight of the UT Southwestern Institutional Animal Care and Use Committee (Protocol # - 2016-101636).

Copyright

© 2019, Jo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Youngah Jo
  2. Jason S Hamilton
  3. Seonghwan Hwang
  4. Kristina Garland
  5. Gennipher A Smith
  6. Shan Su
  7. Iris Fuentes
  8. Sudha Neelam
  9. Bonne M Thompson
  10. Jeffrey G McDonald
  11. Russell A DeBose-Boyd
(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

Share this article

https://doi.org/10.7554/eLife.44396

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Further reading

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    The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase

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    Schnyder corneal dystrophy (SCD) is an autosomal dominant disorder in humans characterized by abnormal accumulation of cholesterol in the cornea. SCD-associated mutations have been identified in the gene encoding UBIAD1, a prenyltransferase that synthesizes vitamin K2. Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER)-associated degradation augmented by the nonsterol isoprenoid geranylgeraniol through an unknown mechanism. Geranylgeraniol inhibits binding of UBIAD1 to reductase, allowing its degradation and promoting transport of UBIAD1 from the ER to the Golgi. CRISPR-CAS9-mediated knockout of UBIAD1 relieves the geranylgeraniol requirement for reductase degradation. SCD-associated mutations in UBIAD1 block its displacement from reductase in the presence of geranylgeraniol, thereby preventing degradation of reductase. The current results identify UBIAD1 as the elusive target of geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD.

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