Hepatitis C virus (HCV) exacts a heavy toll on public health. Approximately 170 million people worldwide are infected persistently with HCV and these individuals account for most cases of chronic liver disease. HCV infection is also the leading cause of liver failure in the United States. The current interferon-based therapies for HCV infection are effective in only a fraction of the patients and are plagued with adverse effects, underscoring the need for new therapeutic strategies
HCV is a single-stranded positive-sense RNA virus of the Flaviviridae family. A major obstacle in combating HCV infection is that the fidelity of the viral replication machinery is notoriously low, which enables the virus to quickly develop mutations that resist compounds targeting viral enzymes. Thus, drugs that target host factors required for HCV infection may be more effective in combating HCV infection. My lab is interested in identifying host proteins that can be targeted by drugs to treat HCV infection without intolerable toxicity and viral resistance.
We have recently revealed that cholesterol metabolism in host cells is tightly linked to the life cycle of HCV. We showed that HCV RNA replication can be disrupted by treatment of cells with lovastatin, a cholesterol lowing drug that inhibits 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in the mevalonate pathway, which is responsible for the cholesterol synthesis in mammalian cells. This inhibition was traced to the depletion of the geranylgeranyl lipid, an isoprenoid produced via the mevalonate pathway. This lipid can be attached to the COOH-terminal cysteine of certain proteins in a post translational modification termed protein geranylgeranylation. We then identified FBL2, a protein of unknown physiological function, as a geranylgeranylated cellular protein required for HCV RNA replication through its interaction with HCV viral protein NS5A.
Another link between HCV infection and cholesterol metabolism in host cells is revealed by our recent discovery that HCV replicates on membrane vesicles involved in the assembly of very low density lipoproteins (VLDL), which is produced in hepatocytes to secret triglyceride and cholesterol. The co-localization of HCV replication and VLDL assembly allows the co-assembly and secretion of HCV and VLDL particles. Thus, treatment of cells with agents that specifically block the secretion of VLDL inhibits HCV production at the same time, suggesting that drugs blocking VLDL secretion may be useful in treating HCV infection.
To further understand the roles of VLDL assembly in HCV infection, we are now trying to determine how VLDL is assembled in hepatoma cells, how HCV is incorporated into VLDL, and the effect of HCV infection on VLDL secretion. Answers to these questions may not only provide new drug targets in combating HCV, but also explain some pathological effects of viral infection.
Inasmuch as cholesterol homeostasis plays an important role in HCV infection, we are also interested in studying the regulation of cholesterol metabolism. To this end, we focused on Insig-1, which is required for the cholesterol-mediated feedback regulation. Particularly, we found that degradation of this protein is regulated by metabolic perturbations. We showed that Insig-1 is ubiquitinated and rapidly degraded in cells depleted of cholesterol, but stabilized in cells repleted of cholesterol owing to dissociation of gp78, an E3 ubiquitin ligase from Insig-1. Other factors, such as fatty acids and cytokines, also appear to regulate the stability of Insig-1. The mechanism of these regulations is one area of the current research.
RESEARCH INTERESTS
Host factors required for HCV replication
Regulation of lipid metabolism
RECENT PUBLICATIONS
Lee, J., Song, B., Debose-Boyd, R., and Ye, J., "Sterol-regulated degradation of Insig-1 mediated by the membrane-bound ubiquitin ligase gp78." J. Biol. Chem., 281:39308-39315, 2006
Huang, H., Sun, F., Owen, D.M., Li, W., Chen, Y., Gale, M., Jr. and Ye, J., "Hepatitis C Virus production by human hepatocytes dependent on assembly and secretion of Very Low Density Lipoproteins." Proc. Natl. Acad. Sci. USA, 104:5848-5853, 2007
Huang, H., Chen, Y., and Ye, J., "Inhibition of hepatitis C virus replication by peroxidation of arachidonate and restoration by vitamin E." Proc. Natl. Acad. Sci. USA, 104:18666-18670, 2007
Ye, Jin, "Reliance of host cholesterol metabolic pathways for the life cycle of hepatitis C virus." PLoS Pathog., 3:1017-1022, 2007
Yao, H. and Ye, J., "Long chain acyl-CoA synthetase 3-mediated phosphatidylcholine synthesis is required for assembly of very low density lipoproteins in human hepatoma Huh7 cells" J. Biol. Chem., 283:849-854, 2008
SIGNIFICANT PUBLICATIONS
Wang C., Hua, H., Gale, M., Brown, M.S., Goldstein, J.L., and Ye, J., "Identification of FBL2 as a geranylgeranylated cellular protein required." Mol. Cell, 18:425-434, 2005
Gong, Y., Lee, J., Lee, P., Goldstein, J.L., Brown, M.S. and Ye, J., "Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feed back control of cholesterol synthesis and uptake." Cell Metabolism, 3:15-24, 2006
Lee, J., Gong, Y., Zhang, X., and Ye, J., "Proteasomal degradation of ubiquitinated Insig proteins is determined by serine residues flanking ubiquitinated lysines." Proc. Natl. Acad. Sci. USA., 103:4958-4963, 2006
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