title: HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type I IFN expression.
abstract: Herpes simplex virus (HSV) 1 stimulates type I IFN expression through the cGAS-STING-TBK1 signaling axis. Macrophages have recently been proposed to be an essential source of IFN during viral infection. However, it is not known how HSV-1 inhibits IFN expression in this cell type. Here, we show that HSV-1 inhibits type I IFN induction through the cGAS-STING-TBK1 pathway in human macrophages, in a manner dependent on the conserved herpesvirus protein ICP27. This viral protein was expressed de novo in macrophages with early nuclear localization followed by later translocation to the cytoplasm where ICP27 prevented activation of IRF3. ICP27 interacted with TBK1 and STING in a manner that was dependent on TBK1 activity and the RGG motif in ICP27. Thus, HSV-1 inhibits expression of type I IFN in human macrophages through ICP27-dependent targeting of the TBK1-activated STING signalsome.
authors.affiliation: Department of Biomedicine, University of Aarhus, Aarhus, Denmark Aarhus Research Center for Innate Immunology, University of Aarhus, Aarhus, Denmark.
authors.forename: Maria H
authors.initials: MH
authors.lastname: Christensen
authors.affiliation: Department of Biomedicine, University of Aarhus, Aarhus, Denmark Aarhus Research Center for Innate Immunology, University of Aarhus, Aarhus, Denmark.
authors.forename: Søren B
authors.initials: SB
authors.lastname: Jensen
authors.affiliation: University of Helsinki, Helsinki, Finland.
authors.forename: Juho J
authors.initials: JJ
authors.lastname: Miettinen
authors.affiliation: Department of Biomedicine, University of Aarhus, Aarhus, Denmark Aarhus Research Center for Innate Immunology, University of Aarhus, Aarhus, Denmark.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Luecke
authors.affiliation: Department of Biomedicine, University of Aarhus, Aarhus, Denmark Aarhus Research Center for Innate Immunology, University of Aarhus, Aarhus, Denmark.
authors.forename: Thaneas
authors.initials: T
authors.lastname: Prabakaran
authors.affiliation: Department of Biomedicine, University of Aarhus, Aarhus, Denmark Aarhus Research Center for Innate Immunology, University of Aarhus, Aarhus, Denmark.
authors.forename: Line S
authors.initials: LS
authors.lastname: Reinert
authors.affiliation: Friedrich-Loeffler-Institut, Insel Riems, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mettenleiter
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Knipe
authors.affiliation: Department of Microbiology & Molecular Genetics, University of California, Irvine, CA, USA.
authors.forename: Rozanne M
authors.initials: RM
authors.lastname: Sandri-Goldin
authors.affiliation: Princeton University, Princeton, NJ, USA.
authors.forename: Lynn W
authors.initials: LW
authors.lastname: Enquist
authors.affiliation: Department of Biomedicine, University of Aarhus, Aarhus, Denmark Aarhus Research Center for Innate Immunology, University of Aarhus, Aarhus, Denmark Department of Molecular Biology and Genetics, Aarhus Research Center for Innate Immunity, Aarhus University, Aarhus, Denmark.
authors.forename: Rune
authors.identifier: 0000-0003-1159-066X
authors.initials: R
authors.lastname: Hartmann
authors.affiliation: Department of Biomedicine, University of Aarhus, Aarhus, Denmark Aarhus Research Center for Innate Immunology, University of Aarhus, Aarhus, Denmark Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: Trine H
authors.initials: TH
authors.lastname: Mogensen
authors.affiliation: Department of Microbiology, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Rice
authors.affiliation: University of Helsinki, Helsinki, Finland.
authors.forename: Tuula A
authors.initials: TA
authors.lastname: Nyman
authors.affiliation: Finnish Institute of Occupational Health, Helsinki, Finland.
authors.forename: Sampsa
authors.initials: S
authors.lastname: Matikainen
authors.affiliation: Department of Biomedicine, University of Aarhus, Aarhus, Denmark Aarhus Research Center for Innate Immunology, University of Aarhus, Aarhus, Denmark srp@biomed.au.dk.
authors.forename: Søren R
authors.identifier: 0000-0001-9180-4060
authors.initials: SR
authors.lastname: Paludan
mesh_terms: D002478:Cells, Cultured; D018259:Herpesvirus 1, Human / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D057131:Immune Evasion; D007370:Interferon Type I / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000276:immunology*; D008565:Membrane Proteins / Q000378:metabolism*; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000099197:STING Protein
chemical_list: D017874:Immediate-Early Proteins; D007370:Interferon Type I; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; C057120:ICP27 protein, human herpesvirus 1; C532857:STING1 protein, human; D000099197:STING Protein; C403191:TBK1 protein, human
keywords: herpes simplex virus; immune evasion; innate immunity; type I IFN