title: Differential, type I interferon-mediated autophagic trafficking of hepatitis C virus proteins in mouse liver.
abstract: OBJECTIVE
  The hepatitis C virus (HCV) serine protease NS3/4A can cleave mitochondria-associated antiviral signaling protein (MAVS) and block retinoic acid-inducible gene I-mediated interferon (IFN) responses. Although this mechanism is thought to have an important role in HCV-mediated innate immunosuppression, its significance in viral persistence is not clear.
  
  
  METHODS
  We generated transgenic mice that express the HCV NS3/4A proteins specifically in the liver and challenged the animals with a recombinant vesicular stomatitis virus, a synthetic HCV genome, IFN alfa, or IFN beta. We evaluated the effects of HCV serine protease on the innate immune responses and their interactions.
  
  
  RESULTS
  Expression of HCV NS3/4A resulted in cleavage of intrahepatic MAVS; challenge of transgenic mice with vesicular stomatitis virus or a synthetic HCV genome induced strong, type I IFN-mediated responses that were not significantly lower than those of control mice. Different challenge agents induced production of different ratios of IFN alfa and beta, resulting in different autophagic responses and vesicular trafficking patterns of endoplasmic reticulum- and mitochondria-associated viral proteins. IFN beta promoted degradation of the viral proteins by the autolysosome. Variant isoforms of MAVS were associated with distinct, type I IFN-mediated autophagic responses; these responses have a role in trafficking of viral components to endosomal compartments that contain Toll-like receptor-3.
  
  
  CONCLUSIONS
  IFN beta mediates a distinct autophagic mechanism of antiviral host defense. MAVS has an important role in type I IFN-induced autophagic trafficking of viral proteins.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, Texas 77555-1019, USA. madesai@utmb.edu
authors.forename: Mayura M
authors.initials: MM
authors.lastname: Desai
authors.forename: Bin
authors.initials: B
authors.lastname: Gong
authors.forename: Tehsheng
authors.initials: T
authors.lastname: Chan
authors.forename: Robert A
authors.initials: RA
authors.lastname: Davey
authors.forename: Lynn
authors.initials: L
authors.lastname: Soong
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Kolokoltsov
authors.forename: Jiaren
authors.initials: J
authors.lastname: Sun
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000276:immunology; D001692:Biological Transport; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000276:immunology; D015870:Gene Expression; D016174:Hepacivirus / Q000276:immunology*; D007113:Immunity, Innate; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology; D016898:Interferon-alpha / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D012367:RNA, Viral / Q000276:immunology*; D011994:Recombinant Proteins; D015398:Signal Transduction; D018116:Vesiculovirus / Q000276:immunology*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D000085242:Viral Proteases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I; D016898:Interferon-alpha; D016899:Interferon-beta; D008869:Microtubule-Associated Proteins; D012367:RNA, Viral; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins; C512612:MAVS protein, mouse; C480860:Map1lc3b protein, mouse; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D000085242:Viral Proteases; C503356:Ddx58 protein, mouse