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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Main Authors: 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
Format: Article
Language:English
Published: eLife Sciences Publications Ltd 2020-03-01
Series:eLife
Subjects:
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.
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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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