title: Hepatitis B virus polymerase suppresses NF-κB signaling by inhibiting the activity of IKKs via interaction with Hsp90β.
abstract: Nuclear factor-κB (NF-κB) plays a central role in the regulation of diverse biological processes, including immune responses, development, cell growth, and cell survival. To establish persistent infection, many viruses have evolved strategies to evade the host's antiviral immune defenses. In the case of hepatitis B virus (HBV), which can cause chronic infection in the liver, immune evasion strategies used by the virus are not fully understood. It has recently been reported that the polymerase of HBV (Pol) inhibits interferon-β (IFN-β) activity by disrupting the interaction between IKKε and the DDX3. In the current study, we found that HBV Pol suppressed NF-κB signaling, which can also contribute to IFN-β production. HBV Pol did not alter the level of NF-κB expression, but it prevented NF-κB subunits involved in both the canonical and non-canonical NF-κB pathways from entering the nucleus. Further experiments demonstrated that HBV Pol preferentially suppressed the activity of the IκB kinase (IKK) complex by disrupting the association of IKK/NEMO with Cdc37/Hsp90, which is critical for the assembly of the IKK complex and recruitment of the IKK complex to the tumor necrosis factor type 1 receptor (TNF-R1). Furthermore, we found that HBV Pol inhibited the NF-κB-mediated transcription of target genes. Taken together, it is suggested that HBV Pol could counteract host innate immune responses by interfering with two distinct signaling pathways required for IFN-β activation. Our studies therefore shed light on a potential therapeutic target for persistent infection with HBV.
authors.affiliation: National Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan City, P. R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: National Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan City, P. R. China.
authors.forename: An'dong
authors.initials: A
authors.lastname: Wu
authors.affiliation: National Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan City, P. R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cui
authors.affiliation: National Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan City, P. R. China.
authors.forename: Ruidong
authors.initials: R
authors.lastname: Hao
authors.affiliation: National Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan City, P. R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan City, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.affiliation: National Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan City, P. R. China.
authors.forename: Deyin
authors.initials: D
authors.lastname: Guo
mesh_terms: D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D015870:Gene Expression; D015684:Gene Products, pol / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006515:Hepatitis B virus / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D015684:Gene Products, pol; D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D016328:NF-kappa B; C066027:P protein, Hepatitis B virus; D051550:I-kappa B Kinase