Enhanced ER-associated degradation of hmg coa reductase causes embryonic lethality associated with ubiad1 deficiency

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

doi:10.7554/eLife.54841

Enhanced ER-associated degradation of hmg coa reductase causes embryonic lethality associated with ubiad1 deficiency

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

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English (US)
Article number	e54841
Journal	eLife
Volume	9
DOIs	https://doi.org/10.7554/eLife.54841
State	Published - Mar 2020

ASJC Scopus subject areas

Neuroscience(all)
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)

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title = "Enhanced ER-associated degradation of hmg coa reductase causes embryonic lethality associated with ubiad1 deficiency",

abstract = "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.",

author = "Youngah Jo and Kim, {Steven S.} and Kristina Garland and Iris Fuentes and Dicarlo, {Lisa M.} and Ellis, {Jessie L.} and Xueyan Fu and Booth, {Sarah L.} and Evers, {Bret M.} and Debose-Boyd, {Russell A.}",

note = "Funding Information: We thank Dr. Guosheng Liang for helpful advice. This work was supported by National Institutes of Health grants HL-20948 (RD-B) and the USDA ARS Cooperative Agreement (58-1950-7-707) (SLB). Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the USDA. Publisher Copyright: {\textcopyright} Jo et al.",

year = "2020",

month = mar,

doi = "10.7554/eLife.54841",

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journal = "eLife",

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AU - Jo, Youngah

AU - Kim, Steven S.

AU - Garland, Kristina

AU - Fuentes, Iris

AU - Dicarlo, Lisa M.

AU - Ellis, Jessie L.

AU - Fu, Xueyan

AU - Booth, Sarah L.

AU - Evers, Bret M.

AU - Debose-Boyd, Russell A.

N1 - Funding Information: We thank Dr. Guosheng Liang for helpful advice. This work was supported by National Institutes of Health grants HL-20948 (RD-B) and the USDA ARS Cooperative Agreement (58-1950-7-707) (SLB). Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the USDA. Publisher Copyright: © Jo et al.

PY - 2020/3

Y1 - 2020/3

N2 - 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.

AB - 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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Enhanced ER-associated degradation of hmg coa reductase causes embryonic lethality associated with ubiad1 deficiency

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