Phosphorylation-Mediated Interaction of Hepatitis C Virus NS5A and the Cellular YB-1 Controls HCV Propagation and the Early Stage of Viral RNA Replication

Abstract

About 130-150 million individuals worldwide are chronically infected by hepatitis C virus (HCV); HCV infection has become a leading cause of liver cirrhosis and hepatocellular carcinoma. The HCV life cycle relies on the cooperation of specific viral proteins and various cellular factors. The cellular protein Y-box binding protein 1 (YB-1) has recently been identified as a HCV host cofactor; however, its mechanism has not been fully characterized. The HCV nonstructural protein NS5A plays critical roles in almost every stage of HCV propagation, and has been proposed to control the switch between the defined stages of the HCV life cycle. Moreover, NS5A has recently emerged as a target for the development of novel anti-HCV drugs. Our studies have found that YB-1 not only interacts with NS5A, but also protects NS5A from degradation. Furthermore, both the NS5A/YB-1 interaction and the NS5A-stabilizing activity of YB-1 are dependent on the phosphorylation of YB-1 at serine 102 (S102). Interestingly, the YB-1 S102 site has previously been reported to be phosphorylated by Akt, which is in turn activated by HCV infection. Our study also reveals that DDX3, an YB-1-interacting partner, is another NS5A-binding protein, which plays a different role than YB-1 in HCV RNA replication and infectious virus production. Taken together, the elucidation of YB-1 participation in the HCV life cycle has led to a proposed mechanism of efficient virus propagation via coordination of the different stages of the viral life cycle through controlling stage-wise switches in the viral life cycle. Our finding also provides a novel niche for designing strategies for the development of new anti-HCV drugs by blocking specific virus-host interactions.