title: The varicella-zoster virus ORF47 kinase interferes with host innate immune response by inhibiting the activation of IRF3.
abstract: The innate immune response constitutes the first line of host defence that limits viral spread and plays an important role in the activation of adaptive immune response. Viral components are recognized by specific host pathogen recognition receptors triggering the activation of IRF3. IRF3, along with NF-κB, is a key regulator of IFN-β expression. Until now, the role of IRF3 in the activation of the innate immune response during Varicella-Zoster Virus (VZV) infection has been poorly studied. In this work, we demonstrated for the first time that VZV rapidly induces an atypical phosphorylation of IRF3 that is inhibitory since it prevents subsequent IRF3 homodimerization and induction of target genes. Using a mutant virus unable to express the viral kinase ORF47p, we demonstrated that (i) IRF3 slower-migrating form disappears; (ii) IRF3 is phosphorylated on serine 396 again and recovers the ability to form homodimers; (iii) amounts of IRF3 target genes such as IFN-β and ISG15 mRNA are greater than in cells infected with the wild-type virus; and (iv) IRF3 physically interacts with ORF47p. These data led us to hypothesize that the viral kinase ORF47p is involved in the atypical phosphorylation of IRF3 during VZV infection, which prevents its homodimerization and subsequent induction of target genes such as IFN-β and ISG15.
authors.affiliation: GIGA-Research, Laboratory of Virology and Immunology, University of Liege, Liege, Belgium.
authors.forename: Patricia
authors.initials: P
authors.lastname: Vandevenne
authors.forename: Marielle
authors.initials: M
authors.lastname: Lebrun
authors.forename: Nadia
authors.initials: N
authors.lastname: El Mjiyad
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ote
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Di Valentin
authors.forename: Yvette
authors.initials: Y
authors.lastname: Habraken
authors.forename: Estelle
authors.initials: E
authors.lastname: Dortu
authors.forename: Jacques
authors.initials: J
authors.lastname: Piette
authors.forename: Catherine
authors.initials: C
authors.lastname: Sadzot-Delvaux
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D014645:Herpesvirus 3, Human / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D050838:Interferon Regulatory Factor-3 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D014764:Viral Proteins / Q000494:pharmacology*
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C503396:ORF47 protein, varicella-zoster virus; D014764:Viral Proteins