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.
Highlights
Vitamin K refers to a group of lipophilic molecules that serve as a cofactor for g-carboxyglutamyl carboxylase, which converts specific glutamate residues in a limited set of proteins to g-carboxyglutamate (Shearer and Newman, 2014; Shearer and Okano, 2018)
In 2015, we showed that Schnyder corneal dystrophy (SCD)-associated UbiA prenyltransferase domain-containing protein-1 (UBIAD1) inhibits the sterol-accelerated, endoplasmic reticulum (ER)-associated degradation (ERAD) of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) (Schumacher et al, 2015), one of several feedback mechanisms that converge on the enzyme to assure cholesterol homeostasis (Brown and Goldstein, 1980)
The genetic ablation of UBIAD1 in transformed human fibroblasts led to enhanced ERAD of HMG CoA reductase (HMGCR) and reduced cholesterol synthesis and intracellular accumulation of cholesterol (Schumacher et al, 2018)
Summary
Vitamin K refers to a group of lipophilic molecules that serve as a cofactor for g-carboxyglutamyl carboxylase, which converts specific glutamate residues in a limited set of proteins to g-carboxyglutamate (Shearer and Newman, 2014; Shearer and Okano, 2018). This post-translational modification is obligatory for biological functions of resultant vitamin K-dependent proteins (VKDPs), some of which play key roles in blood coagulation.
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