title: Hepatitis C virus NS4B blocks the interaction of STING and TBK1 to evade host innate immunity.
abstract: OBJECTIVE
  Hepatitis C virus (HCV) is a major human viral pathogen that causes chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. In most cases, acute HCV infection becomes persistent, at least in part due to viral evasion of host innate immune response. Although HCV genomic RNA contains pathogen-associated molecular pattern (PAMP) that is able to induce host interferon responses, HCV can shut down the responses by using the viral NS3/4A protease to cleave MAVS/VISA and TRIF, two key adaptor molecules essential for the interferon signaling activation. The aim of this study was to explore a novel NS3/4A-independent mechanism HCV utilizes to evade host innate immune responses.
  
  
  METHODS
  We used the interferon promoter-reporter system to screen HCV encoded proteins for their activities to suppress the interferon signaling and to determine the molecular targets of viral proteins. Co-immunoprecipitation, confocal microscopy, and siRNA-based gene silencing were used to investigate the molecular mechanism.
  
  
  RESULTS
  We found that, in addition to NS3/4A, NS4B can suppress double-stranded RNA or RNA virus induced interferon activation. NS4B interacts with STING/MITA, an important molecule that mediates the HCV PAMP induced interferon signaling. Mechanistic studies indicated that NS4B disrupts the interactions between STING/MITA and TBK1.
  
  
  CONCLUSIONS
  In conclusion, we reported an additional mechanism for HCV evasion of host interferon responses in which viral NS4B protein targets STING/MITA to suppress the interferon signaling. Our results present important evidence for the control of interferon response by HCV, and shed more light on the molecular mechanisms underlying the persistence of HCV infection.
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.forename: Xuezhi
authors.initials: X
authors.lastname: Cao
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Bing
authors.initials: B
authors.lastname: Huang
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kato
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shu
authors.forename: Jin
authors.initials: J
authors.lastname: Zhong
mesh_terms: D002460:Cell Line; D057809:HEK293 Cells; D016174:Hepacivirus / Q000201:enzymology / Q000276:immunology* / Q000472:pathogenicity*; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000821:virology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000276:immunology; D007372:Interferons / Q000096:biosynthesis; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000099197:STING Protein
chemical_list: D050838:Interferon Regulatory Factor-3; D007372:Interferons; D008565:Membrane Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D017361:Viral Nonstructural Proteins; C494232:IRF3 protein, human; C080107:NS4B protein, flavivirus; C532857:STING1 protein, human; D000099197:STING Protein; C403191:TBK1 protein, human