DDB1 is a cellular substrate of NS3/4A protease and required for hepatitis C virus replication.

Hepatitis C virus (HCV) infection often causes long-term persistent hepatitis, which eventually leads to liver cirrhosis and hepatocellular carcinoma. HCV-encoded NS3/4A protease plays an important role in HCV immune evasion by cleaving key adapter proteins VISA and TRIF of the RIG-I-like receptors and Toll-like receptors mediated interferon (IFN) induction pathways. To further understand the roles of NS3/4A in HCV life cycle, we identified DDB1 as a cellular substrate of NS3/4A protease by biochemical purification and mass spectrometry analysis. NS3/4A interacted with DDB1 and cleaved DDB1 in HCV-infected cells. Mutagenesis indicated that NS3/4A cleaved DDB1 at the residue of C378. Overexpression of DDB1 potentiated HCV replication, whereas knockdown of DDB1 dramatically inhibited HCV replication. Furthermore, our data indicated that the cleavage of DDB1 by NS3/4A protease was required for HCV replication. Our findings suggest that DDB1 is a cellular substrate of NS3/4A required for HCV replication and provide new insight into the interaction between HCV and host cells.

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