HCV‐Host Cell Interactions: Role of Ebp‐1 in Hepatitis C virus Replication

Abstract

Persistent hepatitis C virus ( HCV) infection leads to chronic hepatitis C (CHC), which often progresses to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The molecular mechanisms that establish chronic HCV infection are poorly understood. Also, the role of specific cellular factors in chronic HCV infection is not well established. We have recently identified a cellular factor ErbB3 binding protein‐1 (Ebp1) that specifically interacts with HCV RNA genome and is inhibitory to HCV replication. Ebp1 is a double stranded RNA binding protein that is a member of a family of proliferation‐regulating proteins. Ebp1 has two isoforms, p42 and p48, which are synthesized from two differently spliced mRNAs from the same gene. Our preliminary results show that overexpression of Ebp1 (the longer as well as the shorter isoform) has a strong negative impact on HCV replication. We also found that Ebp1 binds to the HCV 5′NTR. We established that Ebp1 is mainly localized in the cytosol, a site of HCV replication. Further experiments showed that Ebp1 interacts not only with HCV viral proteins NS5A and NS5B, but also with interferon‐inducible double stranded RNA activated protein kinase PKR, which is critical for cellular antiviral and anti proliferative responses induced by interferon. Taken together our results suggest the critical role of Ebp1 in negatively regulating Hepatitis C virus infection. We propose to further identify the role of PKR in Ebp1 mediated signaling in Hepatitis C virus infection. Elucidation of the role of Ebp1 in activating PKR or vice versa will provide valuable insight into the molecular mechanisms of these interactions and their implication on HCV‐replication and associated pathogenesis.