UbiA prenyltransferase domain-containing protein-1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone-4 (MK-4). Mutations in UBIAD1 cause Schnyder corneal dystrophy (SCD), which is characterized by corneal opacification owing to over-accumulation of cholesterol. Our studies disclosed a key role for UBIAD1 in regulating endoplasmic reticulum (ER)-localized HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids including GGpp. Feedback control of reductase involves sterol-induced ubiquitination, an obligatory reaction for its ER-associated degradation (ERAD) that is augmented by GGpp. Sterols also cause UBIAD1 to bind reductase, which inhibits ERAD and allows continued synthesis of nonsterol isoprenoids in sterol-replete cells. GGpp triggers release of reductase from UBIAD1, enhancing ERAD and stimulating translocation of UBIAD1 to Golgi. SCD-associated UBIAD1 resists GGpp-induced release from reductase and becomes sequestered in ER to inhibit ERAD.
Gene knockout studies in mice were attempted to explore the in vivo function of UBIAD1; however, homozygous germ-line deletion of Ubiad1 caused embryonic lethality. We generated homozygous deletion of Ubiad1in knock-in mice expressing ubiquitination-resistant HMGCR, implying embryonic lethality results from enhanced ERAD of HMGCR. The study of Ubiad1-deficient mice offers the opportunity to determine the physiological significance of UBIAD1-mediated synthesis of MK-4.