title: DDB1 is a cellular substrate of NS3/4A protease and required for hepatitis C virus replication.
abstract: 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.
authors.affiliation: College of Life Sciences, State Key Laboratory of Virology, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Kang
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.forename: Deyin
authors.initials: D
authors.lastname: Guo
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
authors.forename: Jin
authors.initials: J
authors.lastname: Zhong
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shu
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006526:Hepatitis C / Q000821:virology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D014779:Virus Replication; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017361:Viral Nonstructural Proteins; C091435:DDB1 protein, human; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus