Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3: implications for immune evasion.
Viral infection leads to induction of pattern-recognition receptor signaling, which leads to interferon regulatory factor (IRF) activation and ultimately interferon (IFN) production. To establish infection, many viruses have strategies to evade the innate immunity. For the hepatitis B virus (HBV), which causes chronic infection in the liver, the evasion strategy remains uncertain. We now show that HBV polymerase (Pol) blocks IRF signaling, indicating that HBV Pol is the viral molecule that effectively counteracts host innate immune response. In particular, HBV Pol inhibits TANK-binding kinase 1 (TBK1)/IkappaB kinase-epsilon (IKKepsilon), the effector kinases of IRF signaling. Intriguingly, HBV Pol inhibits TBK1/IKKepsilon activity by disrupting the interaction between IKKepsilon and DDX3 DEAD box RNA helicase, which was recently shown to augment TBK1/IKKepsilon activity. This unexpected role of HBV Pol may explain how HBV evades innate immune response in the early phase of the infection. A therapeutic implication of this work is that a strategy to interfere with the HBV Pol-DDX3 interaction might lead to the resolution of life-long persistent infection.
Wang
Haifeng
H
Department of Biochemistry, Yonsei University, Seoul, Korea.
Ryu
Wang-Shick
WS
D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D015684:Gene Products, pol / Q000276:immunology / Q000502:physiology*; D006515:Hepatitis B virus / Q000201:enzymology / Q000276:immunology*; D006801:Humans; D051550:I-kappa B Kinase; D057131:Immune Evasion; D007113:Immunity, Innate; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D051192:Receptors, Pattern Recognition / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000276:immunology
D015684:Gene Products, pol; D050835:Interferon Regulatory Factors; C066027:P protein, Hepatitis B virus; D051192:Receptors, Pattern Recognition; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D051550:I-kappa B Kinase; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases