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- W4225406513 abstract "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 Ubiad1 in 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." @default.
- W4225406513 created "2022-05-05" @default.
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- W4225406513 date "2022-05-01" @default.
- W4225406513 modified "2023-10-15" @default.
- W4225406513 title "The Vitamin K <sub>2</sub> Synthetic Enzyme UBIAD1 Moonlights as a Key Regulator of Cholesterol Synthesis" @default.
- W4225406513 doi "https://doi.org/10.1096/fasebj.2022.36.s1.0i137" @default.
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