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.
Keywords:
DNA-PK; Mouse; Viruses; inflammation; innate immunity; pattern recognition; vaccinia virus.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cytokines / biosynthesis
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Cytokines / immunology
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DNA Repair / immunology
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DNA, Viral / immunology*
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DNA, Viral / metabolism
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DNA-Activated Protein Kinase / deficiency
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DNA-Activated Protein Kinase / genetics
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DNA-Activated Protein Kinase / immunology*
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / immunology*
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Embryo, Mammalian
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Fibroblasts / immunology
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Fibroblasts / virology
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Gene Expression Regulation / immunology*
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Herpesvirus 1, Human / immunology
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Immunity, Innate*
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Influenza A virus / immunology
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Interferon Regulatory Factor-3 / genetics
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Interferon Regulatory Factor-3 / immunology*
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Interferon Type I / genetics
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Interferon Type I / immunology
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics
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Nuclear Proteins / immunology*
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Primary Cell Culture
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / immunology
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Signal Transduction
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V(D)J Recombination
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Vaccinia virus / immunology
Substances
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Cytokines
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DNA, Viral
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DNA-Binding Proteins
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Interferon Regulatory Factor-3
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Interferon Type I
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Irf3 protein, mouse
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Membrane Proteins
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Nuclear Proteins
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Sting1 protein, mouse
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Tbk1 protein, mouse
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DNA-Activated Protein Kinase
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Prkdc protein, mouse
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Protein Serine-Threonine Kinases