title: IFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes.
abstract: Many human cells can sense the presence of exogenous DNA during infection though the cytosolic DNA receptor cyclic GMP-AMP synthase (cGAS), which produces the second messenger cyclic GMP-AMP (cGAMP). Other putative DNA receptors have been described, but whether their functions are redundant, tissue-specific or integrated in the cGAS-cGAMP pathway is unclear. Here we show that interferon-γ inducible protein 16 (IFI16) cooperates with cGAS during DNA sensing in human keratinocytes, as both cGAS and IFI16 are required for the full activation of an innate immune response to exogenous DNA and DNA viruses. IFI16 is also required for the cGAMP-induced activation of STING, and interacts with STING to promote STING phosphorylation and translocation. We propose that the two DNA sensors IFI16 and cGAS cooperate to prevent the spurious activation of the type I interferon response.
authors.affiliation: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.|Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK.
authors.forename: Jessica F
authors.initials: JF
authors.lastname: Almine
authors.affiliation: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.|Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK.
authors.forename: Craig A J
authors.initials: CA
authors.lastname: O'Hare
authors.affiliation: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.|Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: Dunphy
authors.affiliation: The Pirbright Institute, Pirbright, Surrey GU24 0NF, UK.
authors.forename: Ismar R
authors.initials: IR
authors.lastname: Haga
authors.affiliation: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Rangeetha J
authors.initials: RJ
authors.lastname: Naik
authors.affiliation: Fingerprints Proteomics Facility, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Abdelmadjid
authors.initials: A
authors.lastname: Atrih
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Dympna J
authors.initials: DJ
authors.lastname: Connolly
authors.affiliation: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Jordan
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Ian R
authors.identifier: 0000-0002-7501-6504
authors.initials: IR
authors.lastname: Kelsall
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Bowie
authors.affiliation: The Pirbright Institute, Pirbright, Surrey GU24 0NF, UK.|The Roslin Institute and The Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh EH25 9RG, UK.
authors.forename: Philippa M
authors.initials: PM
authors.lastname: Beard
authors.affiliation: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.|Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK.
authors.forename: Leonie
authors.initials: L
authors.lastname: Unterholzner
mesh_terms: D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D004267:DNA Viruses / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009712:Nucleotides, Cyclic / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004247:DNA; D016899:Interferon-beta; D008565:Membrane Proteins; D009687:Nuclear Proteins; D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; D010750:Phosphoproteins; C532857:STING1 protein, human; D000099197:STING Protein; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C076700:IFI16 protein, human; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase