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

Schumacher MM, Elsabrouty R, Seemann J, Jo Y, DeBose-Boyd RA - Elife (2015)

Bottom Line: Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER)-associated degradation augmented by the nonsterol isoprenoid geranylgeraniol through an unknown mechanism.CRISPR-CAS9-mediated knockout of UBIAD1 relieves the geranylgeraniol requirement for reductase degradation.The current results identify UBIAD1 as the elusive target of geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.

ABSTRACT
Schnyder corneal dystrophy (SCD) is an autosomal dominant disorder in humans characterized by abnormal accumulation of cholesterol in the cornea. SCD-associated mutations have been identified in the gene encoding UBIAD1, a prenyltransferase that synthesizes vitamin K2. Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER)-associated degradation augmented by the nonsterol isoprenoid geranylgeraniol through an unknown mechanism. Geranylgeraniol inhibits binding of UBIAD1 to reductase, allowing its degradation and promoting transport of UBIAD1 from the ER to the Golgi. CRISPR-CAS9-mediated knockout of UBIAD1 relieves the geranylgeraniol requirement for reductase degradation. SCD-associated mutations in UBIAD1 block its displacement from reductase in the presence of geranylgeraniol, thereby preventing degradation of reductase. The current results identify UBIAD1 as the elusive target of geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD.

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Biosynthesis of cholesterol and menaquinone-4 (MK-4, vitamin K2) in mammalian cells.DOI:http://dx.doi.org/10.7554/eLife.05560.003
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fig1: Biosynthesis of cholesterol and menaquinone-4 (MK-4, vitamin K2) in mammalian cells.DOI:http://dx.doi.org/10.7554/eLife.05560.003

Mentions: In 2007, two groups independently identified SCD-associated mutations in the gene encoding UBIAD1 (UbiA prenyltransferase domain-containing protein-1) (Orr et al., 2007; Weiss et al., 2007). UBIAD1 (also known as TERE1) was first described as being absent or markedly diminished in bladder and prostate tumors (McGarvey et al., 2001, 2003) and belongs to the UbiA superfamily of prenyltransferases (Heide, 2009). These enzymes, which are found in a wide variety of species, contain 8–10 transmembrane helices and catalyze transfer of isoprenyl groups to aromatic acceptors, producing a diverse range of molecules including ubiquinone, chlorophylls, hemes, vitamin E, and vitamin K (Forsgren et al., 2004; Nakagawa et al., 2010; Bonitz et al., 2011). Indeed, UBIAD1 catalyzes transfer of the 20-carbon geranylgeranyl group from geranylgeranyl pyrophosphate to menadione (vitamin K3) derived from plant-derived phylloquinone (vitamin K1), generating MK-4 (menaquinone-4, vitamin K2) (Figure 1) (Nakagawa et al., 2010; Hirota et al., 2013). It has also been proposed that UBIAD1 mediates polyprenylation of 4-hydroxybenzoate to produce 3-polyprenyl-4-hydroxybenzoate (PPHB), an intermediate in the synthesis of CoQ10 (coenzyme Q10 or ubiquinone-10) (Mugoni et al., 2013).10.7554/eLife.05560.003Figure 1.Biosynthesis of cholesterol and menaquinone-4 (MK-4, vitamin K2) in mammalian cells.


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

Schumacher MM, Elsabrouty R, Seemann J, Jo Y, DeBose-Boyd RA - Elife (2015)

Biosynthesis of cholesterol and menaquinone-4 (MK-4, vitamin K2) in mammalian cells.DOI:http://dx.doi.org/10.7554/eLife.05560.003
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4374513&req=5

fig1: Biosynthesis of cholesterol and menaquinone-4 (MK-4, vitamin K2) in mammalian cells.DOI:http://dx.doi.org/10.7554/eLife.05560.003
Mentions: In 2007, two groups independently identified SCD-associated mutations in the gene encoding UBIAD1 (UbiA prenyltransferase domain-containing protein-1) (Orr et al., 2007; Weiss et al., 2007). UBIAD1 (also known as TERE1) was first described as being absent or markedly diminished in bladder and prostate tumors (McGarvey et al., 2001, 2003) and belongs to the UbiA superfamily of prenyltransferases (Heide, 2009). These enzymes, which are found in a wide variety of species, contain 8–10 transmembrane helices and catalyze transfer of isoprenyl groups to aromatic acceptors, producing a diverse range of molecules including ubiquinone, chlorophylls, hemes, vitamin E, and vitamin K (Forsgren et al., 2004; Nakagawa et al., 2010; Bonitz et al., 2011). Indeed, UBIAD1 catalyzes transfer of the 20-carbon geranylgeranyl group from geranylgeranyl pyrophosphate to menadione (vitamin K3) derived from plant-derived phylloquinone (vitamin K1), generating MK-4 (menaquinone-4, vitamin K2) (Figure 1) (Nakagawa et al., 2010; Hirota et al., 2013). It has also been proposed that UBIAD1 mediates polyprenylation of 4-hydroxybenzoate to produce 3-polyprenyl-4-hydroxybenzoate (PPHB), an intermediate in the synthesis of CoQ10 (coenzyme Q10 or ubiquinone-10) (Mugoni et al., 2013).10.7554/eLife.05560.003Figure 1.Biosynthesis of cholesterol and menaquinone-4 (MK-4, vitamin K2) in mammalian cells.

Bottom Line: Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER)-associated degradation augmented by the nonsterol isoprenoid geranylgeraniol through an unknown mechanism.CRISPR-CAS9-mediated knockout of UBIAD1 relieves the geranylgeraniol requirement for reductase degradation.The current results identify UBIAD1 as the elusive target of geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.

ABSTRACT
Schnyder corneal dystrophy (SCD) is an autosomal dominant disorder in humans characterized by abnormal accumulation of cholesterol in the cornea. SCD-associated mutations have been identified in the gene encoding UBIAD1, a prenyltransferase that synthesizes vitamin K2. Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER)-associated degradation augmented by the nonsterol isoprenoid geranylgeraniol through an unknown mechanism. Geranylgeraniol inhibits binding of UBIAD1 to reductase, allowing its degradation and promoting transport of UBIAD1 from the ER to the Golgi. CRISPR-CAS9-mediated knockout of UBIAD1 relieves the geranylgeraniol requirement for reductase degradation. SCD-associated mutations in UBIAD1 block its displacement from reductase in the presence of geranylgeraniol, thereby preventing degradation of reductase. The current results identify UBIAD1 as the elusive target of geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD.

Show MeSH
Related in: MedlinePlus