Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency
UbiA prenyltransferase domain-containing protein-1 (UBIAD1) synthesizes 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 reduct...
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eLife Sciences Publications Ltd
2020-03-01
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Online Access: | https://elifesciences.org/articles/54841 |
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author | Youngah Jo Steven S Kim Kristina Garland Iris Fuentes Lisa M DiCarlo Jessie L Ellis Xueyan Fu Sarah L Booth Bret M Evers Russell A DeBose-Boyd |
author_facet | Youngah Jo Steven S Kim Kristina Garland Iris Fuentes Lisa M DiCarlo Jessie L Ellis Xueyan Fu Sarah L Booth Bret M Evers Russell A DeBose-Boyd |
author_sort | Youngah Jo |
collection | DOAJ |
description | UbiA prenyltransferase domain-containing protein-1 (UBIAD1) synthesizes 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. |
first_indexed | 2024-04-11T09:17:59Z |
format | Article |
id | doaj.art-51b7cf25cab44a3087a535fad64d36fb |
institution | Directory Open Access Journal |
issn | 2050-084X |
language | English |
last_indexed | 2024-04-11T09:17:59Z |
publishDate | 2020-03-01 |
publisher | eLife Sciences Publications Ltd |
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series | eLife |
spelling | doaj.art-51b7cf25cab44a3087a535fad64d36fb2022-12-22T04:32:17ZengeLife Sciences Publications LtdeLife2050-084X2020-03-01910.7554/eLife.54841Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiencyYoungah Jo0https://orcid.org/0000-0001-6779-3891Steven S Kim1Kristina Garland2Iris Fuentes3Lisa M DiCarlo4Jessie L Ellis5Xueyan Fu6Sarah L Booth7Bret M Evers8https://orcid.org/0000-0001-5686-0315Russell A DeBose-Boyd9https://orcid.org/0000-0002-7452-5227Department of Molecular Genetics, University of Texas Southwestern Medical, Dallas, United StatesDepartment of Molecular Genetics, University of Texas Southwestern Medical, Dallas, United StatesDepartment of Molecular Genetics, University of Texas Southwestern Medical, Dallas, United StatesDepartment of Molecular Genetics, University of Texas Southwestern Medical, Dallas, United StatesDepartment of Molecular Genetics, University of Texas Southwestern Medical, Dallas, United StatesCenter at Dallas and Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Somerville, United StatesCenter at Dallas and Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Somerville, United StatesCenter at Dallas and Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Somerville, United StatesDepartment of Pathology, University of Texas Southwestern Medical, Dallas, United StatesDepartment of Molecular Genetics, University of Texas Southwestern Medical, Dallas, United StatesUbiA prenyltransferase domain-containing protein-1 (UBIAD1) synthesizes 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.https://elifesciences.org/articles/54841isoprenoidvitamin Kembryonic lethalitycholesterol |
spellingShingle | Youngah Jo Steven S Kim Kristina Garland Iris Fuentes Lisa M DiCarlo Jessie L Ellis Xueyan Fu Sarah L Booth Bret M Evers Russell A DeBose-Boyd Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency eLife isoprenoid vitamin K embryonic lethality cholesterol |
title | Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency |
title_full | Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency |
title_fullStr | Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency |
title_full_unstemmed | Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency |
title_short | Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency |
title_sort | enhanced er associated degradation of hmg coa reductase causes embryonic lethality associated with ubiad1 deficiency |
topic | isoprenoid vitamin K embryonic lethality cholesterol |
url | https://elifesciences.org/articles/54841 |
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