title: DNA-PK is a DNA sensor for IRF-3-dependent innate immunity.
abstract: Innate immunity is the first immunological defence against pathogens. During virus infection detection of nucleic acids is crucial for the inflammatory response. Here we identify DNA-dependent protein kinase (DNA-PK) as a DNA sensor that activates innate immunity. We show that DNA-PK acts as a pattern recognition receptor, binding cytoplasmic DNA and triggering the transcription of type I interferon (IFN), cytokine and chemokine genes in a manner dependent on IFN regulatory factor 3 (IRF-3), TANK-binding kinase 1 (TBK1) and stimulator of interferon genes (STING). Both cells and mice lacking DNA-PKcs show attenuated cytokine responses to both DNA and DNA viruses but not to RNA or RNA virus infection. DNA-PK has well-established functions in the DNA repair and V(D)J recombination, hence loss of DNA-PK leads to severe combined immunodeficiency (SCID). However, we now define a novel anti-microbial function for DNA-PK, a finding with implications for host defence, vaccine development and autoimmunity.DOI:http://dx.doi.org/10.7554/eLife.00047.001.
authors.affiliation: Department of Virology ,  Imperial College London ,  London ,  United Kingdom ; Department of Pathology ,  University of Cambridge ,  Cambridge ,  United Kingdom.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Ferguson
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Mansur
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Peters
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ren
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Smith
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004260:DNA Repair / Q000276:immunology; D004279:DNA, Viral / Q000276:immunology* / Q000378:metabolism; D051747:DNA-Activated Protein Kinase / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D005786:Gene Expression Regulation / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology; D007113:Immunity, Innate; D009980:Influenza A virus / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology*; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D060152:V(D)J Recombination; D014616:Vaccinia virus / Q000276:immunology; D000099197:STING Protein
chemical_list: D016207:Cytokines; D004279:DNA, Viral; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008565:Membrane Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; C494233:Irf3 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C498588:Tbk1 protein, mouse; C497264:Prkdc protein, mouse