Significance of UBIAD1 in Regulation of HMG CoA Reductase Degradation, Mevalonate Metabolism, and Menaquinone-4 Synthesis

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UbiA prenyltransferase domain-containing protein-1 (UBIAD1) uses the nonsterol isoprenoid geranylgeranyl pyrophosphate (GGpp) to synthesize a form of vitamin K called menaquinone-4 (MK-4). UBIAD1 is multifunctional as indicated by the association of mutations in human UBIAD1 with Schnyder corneal dystrophy (SCD). This rare autosomal dominant eye disease is characterized by progressive corneal opacification owing to abnormal accumulation of cholesterol. Our studies revealed that sterols cause UBIAD1 to bind endoplasmic reticulum (ER)-localized HMG CoA reductase (HMGCR), the rate-limiting enzyme in synthesis of cholesterol and essential nonsterol isoprenoids including farnesyl pyrophosphate, GGpp, MK-4, ubiquinone, and dolichol. Sterol- induced ubiquitination is obligatory for ER-associated degradation (ERAD) of HMGCR that is augmented by GGpp and constitutes one mechanism for feedback control of the enzyme. GGpp blocks sterol-induced binding of UBIAD1 to HMGCR, which enhances its ERAD and permits ER-to-Golgi transport of UBIAD1. SCD- associated mutants of UBIAD1 resist GGpp-induced displacement from HMGCR and remain sequestered in the ER to inhibit ERAD, which contributes to enhanced synthesis and intracellular accumulation of cholesterol. Gene knockout studies in mice were attempted to elucidate the role of UBIAD1 in tissue-specific distribution of MK-4, which remains a major unresolved question in vitamin K biology. However, homozygous germ-line deletion of Ubiad1 caused embryonic lethality. We recently generated homozygous deletion of Ubiad1 in knock- in mice expressing ubiquitination-resistant HMGCR, which implies embryonic lethality associated with Ubiad1 deficiency results from enhanced ERAD of HMGCR and depletion of mevalonate metabolites distinct from MK- 4. We will now elucidate tissue-specific roles of UBIAD1 in regulating HMGCR ERAD and MK-4 synthesis by pursuing the following Specific Aims: 1) Explore role of UBIAD1-mediated sensing of GGpp in regulation of HMGCR ERAD and mevalonate metabolism in the liver; 2) Determine contribution of UBIAD1-mediated synthesis of MK-4 to skeletal muscle homeostasis; 3) Establish roles for UBIAD1 in pancreatic subsistence and function; and 4) Examine role of UBIAD1 in morphology and function of the intestine. Combined efforts of the PIs, who have complementary expertise in mechanisms underlying regulation of cholesterol metabolism (DeBose-Boyd) and vitamin K biology (Booth), will lead to discovery of tissue-specific pathways/processes modulated by MK-4. In addition, these studies will have immediate clinical implications. HMGCR is the target of statins, widely prescribed drugs that lower plasma LDL-cholesterol and reduce incidence of cardiovascular disease (CVD). However, statins trigger responses that cause accumulation of HMGCR, which blunts their clinical effects. Part of this increase results from UBIAD1-mediated inhibition of HMGCR ERAD. Our studies may expose UBIAD1-mediating sensing of GGpp as a target of therapies that prevent statin-induced accumulation of HMGCR, increasing statin efficacy and ultimately reducing incidence of CVD and heart attacks.