We show that HCV E2 protein induces rapid ezrin phosphorylation and its cellular
redistribution with F-actin by way of spleen tyrosine kinase (SYK). Therapeutically blocking the functional roles of SYK or F-actin reorganization significantly reduced Barasertib price Huh7.5 cell susceptibility to HCV J6/JFH-1 infection. Using gene regulation, real-time quantitative polymerase chain reaction, western blot, and fluorescent microscopy analysis, we found that proteins of the EMR family differentially regulate HCV infection in the J6/JFH-1/Huh7.5 cell system. Moesin and radixin, but not ezrin, expression were significantly decreased in chronic HCV J6/JFH-1-infected Huh7.5 cells and HCV-infected patient liver biopsies compared to controls. The decreases in moesin and radixin in HCV J6/JFH-1-infected Huh7.5 cells were associated with a significant increase in stable microtubules. Ezrin knockdown inhibited immediate Lenvatinib postentry events in HCV infection. Overexpression
of moesin or radixin significantly reduced HCV protein expression. In contrast, transient knockdown of moesin or radixin augmented HCV infection. Making use of the Con1 HCV replicon system, we tested the effect of EMR proteins on HCV replication. We found that transient knockdown of moesin increased HCV RNA expression while overexpression of EMR showed no significant effect on HCV replication. Conclusion: Our findings demonstrate the important role of EMR proteins during HCV infection at the postentry level and highlight possible novel targets for HCV treatment. (Hepatology 2013;58:1569–1579) Hepatitis C virus (HCV) infection is a leading cause of liver disease, with at least 2%–3% of the world’s population chronically infected. Virus elimination through therapy can be limited by several factors, including adverse Rebamipide side effects to current drugs, viral resistance, patient alcohol abuse, and high cost of therapy.[2-6] Chronic HCV infection progressively leads to liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and ultimately death. Viruses, including HCV, exploit host factors and interact with cell surface
or intracellular proteins to achieve effective infection and/or replication.[8-10] Recently, numerous host proteins/peptides have been identified that possess potent antiviral properties.[8, 11-13] Indeed, host proteins/peptides have emerged as alternatives to conventional antiviral agents and present advantages over currently used antiviral drugs such as selective cytotoxicity for the target virus or virus-infected cells, bypassing multidrug-resistance mechanisms and inducing minimal side effects.[11, 13] The HCV virus, a single-stranded positive-sense RNA virus of the Flaviviridae family, was initially identified and distinguished from hepatitis A/B virus infections based on its characteristic induction of microtubule paracrystalline aggregates in infected hepatocytes and liver biopsies of HCV-infected patients.