DNA-PK is a DNA sensor for IRF-3-dependent innate immunity

Elife. 2012 Dec 18;1:e00047. doi: 10.7554/eLife.00047.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • DNA Repair / immunology
  • DNA, Viral / immunology*
  • DNA, Viral / metabolism
  • DNA-Activated Protein Kinase / deficiency
  • DNA-Activated Protein Kinase / genetics
  • DNA-Activated Protein Kinase / immunology*
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology*
  • Embryo, Mammalian
  • Fibroblasts / immunology
  • Fibroblasts / virology
  • Gene Expression Regulation / immunology*
  • Herpesvirus 1, Human / immunology
  • Immunity, Innate*
  • Influenza A virus / immunology
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / immunology*
  • Interferon Type I / genetics
  • Interferon Type I / immunology
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics
  • Nuclear Proteins / immunology*
  • Primary Cell Culture
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / immunology
  • Signal Transduction
  • V(D)J Recombination
  • Vaccinia virus / immunology

Substances

  • Cytokines
  • DNA, Viral
  • DNA-Binding Proteins
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Irf3 protein, mouse
  • MPYS protein, mouse
  • Membrane Proteins
  • Nuclear Proteins
  • Tbk1 protein, mouse
  • DNA-Activated Protein Kinase
  • Prkdc protein, mouse
  • Protein-Serine-Threonine Kinases