Abstract
Hepatitis B virus (HBV) is regarded as a stealth virus, invading and replicating efficiently in human liver undetected by host innate antiviral immunity. Here, we show that type I interferon (IFN) induction but not its downstream signaling is blocked by HBV replication in HepG2.2.15 cells. This effect may be partially due to HBV X protein (HBx), which impairs IFNβ promoter activation by both Sendai virus (SeV) and components implicated in signaling by viral sensors. As a deubiquitinating enzyme (DUB), HBx cleaves Lys63-linked polyubiquitin chains from many proteins except TANK-binding kinase 1 (TBK1). It binds and deconjugates retinoic acid-inducible gene I (RIG I) and TNF receptor-associated factor 3 (TRAF3), causing their dissociation from the downstream adaptor CARDIF or TBK1 kinase. In addition to RIG I and TRAF3, HBx also interacts with CARDIF, TRIF, NEMO, TBK1, inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon (IKKi) and interferon regulatory factor 3 (IRF3). Our data indicate that multiple points of signaling pathways can be targeted by HBx to negatively regulate production of type I IFN.
MeSH terms
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Animals
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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Cell Line
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DEAD Box Protein 58
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DEAD-box RNA Helicases / antagonists & inhibitors
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DEAD-box RNA Helicases / immunology
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DEAD-box RNA Helicases / metabolism
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Hep G2 Cells
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Hepatitis B virus / immunology
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Hepatitis B virus / metabolism
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Humans
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I-kappa B Kinase / antagonists & inhibitors
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I-kappa B Kinase / immunology
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I-kappa B Kinase / metabolism
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Immune Evasion
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Immunity, Innate
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Interferon Regulatory Factor-3 / antagonists & inhibitors
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Interferon Regulatory Factor-3 / immunology
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Interferon Regulatory Factor-3 / metabolism
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Interferon Type I / antagonists & inhibitors*
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Interferon Type I / immunology
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Interferon Type I / metabolism
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Mice
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Molecular Targeted Therapy
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Polyubiquitin / antagonists & inhibitors
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Polyubiquitin / metabolism
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Protein Binding / immunology
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Receptors, Immunologic
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Sendai virus / immunology
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Sendai virus / metabolism
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Signal Transduction / immunology*
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TNF Receptor-Associated Factor 3 / antagonists & inhibitors
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TNF Receptor-Associated Factor 3 / immunology
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TNF Receptor-Associated Factor 3 / metabolism
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Trans-Activators / immunology*
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Trans-Activators / metabolism*
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Viral Regulatory and Accessory Proteins
Substances
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Interferon Regulatory Factor-3
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Interferon Type I
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Receptors, Immunologic
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TNF Receptor-Associated Factor 3
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Trans-Activators
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Viral Regulatory and Accessory Proteins
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hepatitis B virus X protein
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Polyubiquitin
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I-kappa B Kinase
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RIGI protein, human
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DEAD Box Protein 58
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DEAD-box RNA Helicases