Schnyder corneal dystrophy (SCD) is a rare autosomal dominant eye disease characterized by progressive opacification of the cornea owing to abnormal accumulation of cholesterol. Mutations associated with SCD have been identified in the gene encoding UbiA prenyltransferase domain-containing protein-1 (UBIAD1), which utilizes the nonsterol isoprenoid geranylgeranyl pyrophosphate (GGpp) to synthesize vitamin K2. Preliminary studies reveal that sterols trigger binding of UBIAD1 to the enzyme HMG CoA reductase in endoplasmic reticulum (ER) membranes. Reductase produces mevalonate, an important intermediate in synthesis of cholesterol and essential nonsterol isoprenoids such as ubiquinone, vitamin K2, dolichol, and the farnesyl and geranylgeranyl groups that are attached to many cellular proteins. Sterol-regulated ubiquitination is obligatory for ER-associated degradation (ERAD) of reductase, which is augmented by GGpp. This ERAD constitutes one of several mechanisms by which sterol and nonsterol isoprenoids mediate feedback regulation of reductase. GGpp blocks sterol-induced binding of UBIAD1 to reductase, allowing reductase ERAD and UBIAD1 transport from ER to Golgi. Eliminating expression of UBIAD1 relieves the GGpp requirement for reductase ERAD, indicating the reaction is inhibited by the prenyltransferase. SCD-associated mutants of UBIAD1 resist GGpp-induced displacement from reductase and remain sequestered in the ER, thereby inhibiting sterol-accelerated ERAD. Building on these observations, studies are now proposed to elucidate mechanisms through which GGpp regulates intracellular trafficking of UBIAD1 and determine how this regulation impacts synthesis of vitamin K2 and cholesterol. To achieve this, we will pursue the following Specific Aims: 1) Elucidate mechanism through which geranylgeranyl pyrophosphate governs intracellular transport of UBIAD1; 2) Determine significance of ER to Golgi transport of UBIAD1; and 3) Examine role for UBIAD1 as membrane sensor of geranylgeranyl pyrophosphate. Collectively, these studies will provide key information regarding mechanisms through which synthesis of sterol and nonsterol isoprenoids is controlled through regulated transport of UBIAD1 between ER and Golgi. In addition, these studies have significant clinical implications. Reductase is the target of statins, widely prescribed drugs that lower plasma LDL-cholesterol and reduce incidence of cardiovascular disease. Statin-mediated inhibition of reductase also reverses malignant phenotype of certain types of cancer cells. However, statins trigger responses that cause accumulation of reductase, which blunts their clinical effects. Part of this increase results from slowed ERAD of reductase. Thus, elucidating mechanisms for reductase ERAD holds promise for development of new therapies that increase the effectiveness of statins and ultimately reduce the incidence of heart attacks and tumorigenesis. Moreover, insight into mechanisms for reductase ERAD may lead to therapeutic interventions that retard or prevent corneal accumulation of cholesterol associated with SCD.
Cholesterol synthesis requires more than 20 enzymes. The key enzyme, HMG CoA reductase, is controlled through multiple mechanisms, including regulation of protein stability. Statins, competitive inhibitors of reductase, are routinely used t lower blood cholesterol in humans. These drugs also inhibit growth of some cancer cells. However, statins cause an accumulation of reductase protein that blunts their beneficial effects. Part of this increase is due to slowed degradation of reductase. This grant will investigate mechanisms through which the vitamin K2 synthetic enzyme UBIAD1 modulates reductase degradation. Results of proposed studies will provide insight into development of therapies that counteract statin-induced accumulation of reductase and improve their effectiveness. Moreover, these studies will provide insight into therapies to prevent corneal accumulation of cholesterol associated with the eye disease Schnyder corneal dystrophy, which results from mutations in UBIAD1.
| Schumacher, Marc M; Jun, Dong-Jae; Jo, Youngah et al. (2016) Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi. J Lipid Res 57:1286-99 |
