1. Developmental Biology

Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency

  1. Youngah Jo
  2. Steven S Kim
  3. Kristina Garland
  4. Iris Fuentes
  5. Lisa M DiCarlo
  6. Jessie L Ellis
  7. Xueyan Fu
  8. Sarah L Booth
  9. Bret M Evers
  10. Russell A DeBose-Boyd  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. Tufts University, United States
https://doi.org/10.7554/eLife.54841
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Cite this article
  1. Youngah Jo
  2. Steven S Kim
  3. Kristina Garland
  4. Iris Fuentes
  5. Lisa M DiCarlo
  6. Jessie L Ellis
  7. Xueyan Fu
  8. Sarah L Booth
  9. Bret M Evers
  10. Russell A DeBose-Boyd
(2020)
Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency
eLife 9:e54841.
https://doi.org/10.7554/eLife.54841
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  3. Download .RIS

Abstract

UbiA prenyltransferase domain-containing protein-1 (UBIAD1) catalyzes synthesis of the vitamin K subtype menaquinone-4 (MK-4). Previous studies in cultured cells (Schumacher et al. 2015) revealed that UBIAD1 also inhibits endoplasmic reticulum (ER)-associated degradation (ERAD) of ubiquitinated HMG CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway that produces cholesterol and essential nonsterol isoprenoids. Gene knockout studies were previously attempted to explore the function of UBIAD1 in mice; however, homozygous germ-line elimination of the Ubiad1 gene caused embryonic lethality. We now report that homozygous deletion of Ubiad1 is produced in knockin mice expressing ubiquitination/ERAD-resistant HMGCR. Thus, embryonic lethality of Ubiad1 deficiency results from depletion of mevalonate-derived products owing to enhanced ERAD of HMGCR rather than from reduced synthesis of MK-4. These findings provide genetic evidence for the significance of UBIAD1 in regulation of cholesterol synthesis and offer the opportunity in future studies for the discovery of new physiological roles of MK-4.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6779-3891

  2. Steven S Kim

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

  3. 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.

  4. 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.

  5. Lisa M DiCarlo

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

  6. Jessie L Ellis

    Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Xueyan Fu

    Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Sarah L Booth

    Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Bret M Evers

    Pathology, 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:" 0000-0001-5686-0315

  10. 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

U.S. Department of Agriculture (58-1950-7-707)

  • Sarah L Booth

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

Reviewing Editor

  1. Ramanujan S Hegde, MRC Laboratory of Molecular Biology, United Kingdom

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2016-101636) of the University of Texas Southwestern Medical Center.

Version history

  1. Received: January 2, 2020
  2. Accepted: March 2, 2020
  3. Accepted Manuscript published: March 2, 2020 (version 1)
  4. Version of Record published: March 13, 2020 (version 2)

Copyright

© 2020, 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. Steven S Kim
  3. Kristina Garland
  4. Iris Fuentes
  5. Lisa M DiCarlo
  6. Jessie L Ellis
  7. Xueyan Fu
  8. Sarah L Booth
  9. Bret M Evers
  10. Russell A DeBose-Boyd
(2020)
Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency
eLife 9:e54841.
https://doi.org/10.7554/eLife.54841

Share this article

https://doi.org/10.7554/eLife.54841

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

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