title: Canine hepacivirus NS3 serine protease can cleave the human adaptor proteins MAVS and TRIF.
abstract: Canine hepacivirus (CHV) was recently identified in domestic dogs and horses. The finding that CHV is genetically the virus most closely related to hepatitis C virus (HCV) has raised the question of whether HCV might have evolved as the result of close contact between dogs and/or horses and humans. The aim of this study was to investigate whether the NS3/4A serine protease of CHV specifically cleaves human mitochondrial antiviral signaling protein (MAVS) and Toll-IL-1 receptor domain-containing adaptor inducing interferon-beta (TRIF). The proteolytic activity of CHV NS3/4A was evaluated using a bacteriophage lambda genetic screen. Human MAVS- and TRIF-specific cleavage sites were engineered into the lambda cI repressor. Upon infection of Escherichia coli cells coexpressing these repressors and a CHV NS3/4A construct, lambda phage replicated up to 2000-fold more efficiently than in cells expressing a CHV protease variant carrying the inactivating substitution S139A. Comparable results were obtained when several HCV NS3/4A constructs of genotype 1b were assayed. This indicates that CHV can disrupt the human innate antiviral defense signaling pathway and suggests a possible evolutionary relationship between CHV and HCV.
authors.affiliation: Fundació irsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona (UAB), Badalona, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Parera
authors.forename: Gloria
authors.initials: G
authors.lastname: Martrus
authors.forename: Sandra
authors.initials: S
authors.lastname: Franco
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Martinez
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006516:Adenoviruses, Canine / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D000818:Animals; D004285:Dogs; D016174:Hepacivirus / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D059748:Proteolysis; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C505371:MAVS protein, human; D011994:Recombinant Proteins; C470409:TICAM1 protein, human; D017361:Viral Nonstructural Proteins; D012697:Serine Endopeptidases