Russell DeBose-Boyd, PhD (UT Southwestern Medical Center) Webinar

The Vitamin K2 Synthetic Enzyme UBIAD1 Moonlights as a Key Regulator of Cholesterol Synthesis
Nov 23, 2020, 12:00 pm1:00 pm
Thomas Laboratory
Free and open to the university community and the public.


Russell DeBose-Boyd
Professor, Beatrice and Miguel Elias Distinguished Chair in Biomedical Science Department of Molecular Genetics, University of Texas Southwestern Medical Center
University of Texas, Southwestern Medical School


Event Description

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.

Nieng Yan, Department of Molecular Biology
Event Category
Butler Seminar Series