Study Of The Relaionship Between Hepatitis C Virus Infection And The Major Vault Protein

Hepatitis C virus (HCV) infection has become a major problem of public health with more than170million infected individuals worldwide, including over30million in China. Major vault protein (MVP) is the major constituent of vaults and is involved in multidrug resistance, nucleocytoplasmic transport, and cell signaling. However, little is known about the role of MVP during viral infections.To determine the correlation between HCV infection and MVP expression, we examined MVP mRNA levels in PBMCs of healthy participants and HCV patients, and found that MVP mRNA levels were significantly higher in HCV patients. MVP protein expression was also elevated in the sera and liver tissues of HCV patients. Huh7and Huh7.5.1cell lines are an effective cell culture model of HCV infection. Thus, we next infected Huh7cells and Huh7.5.1cells with a HCV genotype2a replicon (JFH-1) and measured the expression of MVP. JFH-1expression induced MVP mRNA and protein expression in a time-and dose-dependent manner. To explore the mechanisms behind HCV upregulated MVP, we constructed the gene promoters of MVP by PCR, and inserted them into the reporter plasmid pGL3-basic. We found that HCV protein NS5A can positively affect MVP promoter activities. Further studies demonstrated that the NF-κB and Spl pathways are involved in the induction of MVP expression by the HCV protein NS5AInterestingly, MVP expression suppressed HCV replication and protein synthesis via induction of type-I interferon mRNA expression and protein secretion. Upon investigating the mechanisms behind this event, we found that overexpression MVP enhanced the expression of IRF7, but not IRF3. Translocation of activated IRF7and NF-KB from the cytosol to the nucleus was involved in this process. Whereas knockdown of MVP inhibited vesicular stomatitis virus-triggered activation of IRF7/NF-κB expression and nuclear-cytoplasmic transportion and type-I interferon mRNA expression and protein secretion. Furthermore, vesicular stomatitis virus, influenza A virus, and enterovirus71also induced MVP production, and MVP in turn hampered viral replication and production. Conclusion:MVP is a novel virus-induced host factor and its expression upregulates type-I interferon production, leading to cellular antiviral responses.Although more studies are needed to understand the delicate regulatory mechanisms of MVP in viral replication and antiviral responses, our findings reveal a previously-undescribed role for MVP in the regulation of cellular antiviral responses. They are also important for establishing novel HCV therapeutic approaches.