title: Contribution of double-stranded RNA and CPSF30 binding domains of influenza virus NS1 to the inhibition of type I interferon production and activation of human dendritic cells.
abstract: The influenza virus nonstructural protein 1 (NS1) inhibits innate immunity by multiple mechanisms. We previously reported that NS1 is able to inhibit the production of type I interferon (IFN) and proinflammatory cytokines in human primary dendritic cells (DCs). Here, we used recombinant viruses expressing mutant NS1 from the A/Texas/36/91 and A/Puerto Rico/08/34 strains in order to analyze the contribution of different NS1 domains to its antagonist functions. We show that the polyadenylation stimulating factor 30 (CPSF30) binding function of the NS1 protein from A/Texas/36/91 influenza virus, which is absent in the A/Puerto Rico/08/34 strain, is essential for counteracting these innate immune events in DCs. However, the double-stranded RNA (dsRNA) binding domain, present in both strains, specifically inhibits the induction of type I IFN genes in infected DCs, while it is essential only for inhibition of type I IFN proteins and proinflammatory cytokine production in cells infected with influenza viruses lacking a functional CPSF30 binding domain, such as A/Puerto Rico/08/34.
authors.affiliation: Department of Microbiology, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, New York, USA. irene.ramos-lopez@mssm.edu
authors.forename: Irene
authors.initials: I
authors.lastname: Ramos
authors.forename: Elena
authors.initials: E
authors.lastname: Carnero
authors.forename: Dabeiba
authors.initials: D
authors.lastname: Bernal-Rubio
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Seibert
authors.forename: Liset
authors.initials: L
authors.lastname: Westera
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandez-Sesma
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D039223:Cleavage And Polyadenylation Specificity Factor / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D004285:Dogs; D006801:Humans; D007113:Immunity, Innate; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D007370:Interferon Type I / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis; D061985:Madin Darby Canine Kidney Cells; D016328:NF-kappa B / Q000096:biosynthesis; D017434:Protein Structure, Tertiary; D012330:RNA, Double-Stranded / Q000378:metabolism*; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D039223:Cleavage And Polyadenylation Specificity Factor; C085820:INS1 protein, influenza virus; D007370:Interferon Type I; D015850:Interleukin-6; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha; D017361:Viral Nonstructural Proteins