117.2 - The Vitamin K2 Synthetic Enzyme UBIAD1 Moonlights as a Key Regulator of Cholesterol Synthesis

Russell DeBose-Boyd (University of Texas Southwest Medical Center), Youngah Jo (University of Texas Southwestern Medical Center), Marc Schumacher (University of Texas Southwestern Medical Center)

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. 

Support or Funding Information

This work is supported by the following grants from the National Institutes of Health:  P01 HL020948, R01 GM134700, and R01 GM144039.

This work is supported by the following grants from the National Institutes of Health: amp;nbsp;P01 HL020948,amp;nbsp;R01 GM134700, andamp;nbsp;R01 GM144039.