Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency
- University of Texas Southwestern Medical Center, United States
- Tufts University, United States
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Russell A DeBose-Boyd
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
- 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
- Received: January 2, 2020
- Accepted: March 2, 2020
- Accepted Manuscript published: March 2, 2020 (version 1)
- 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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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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