Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1β production

Nat Immunol. 2014 Jun;15(6):538-45. doi: 10.1038/ni.2888. Epub 2014 Apr 28.

Abstract

Double-stranded DNA (dsDNA) in the cytoplasm triggers the production of interleukin 1β (IL-1β) as an antiviral host response, and deregulation of the pathways involved can promote inflammatory disease. Here we report a direct cytosolic interaction between the DNA-damage sensor Rad50 and the innate immune system adaptor CARD9. Transfection of dendritic cells with dsDNA or infection of dendritic cells with a DNA virus induced the formation of dsDNA-Rad50-CARD9 signaling complexes for activation of the transcription factor NF-κB and the generation of pro-IL-1β. Primary cells conditionally deficient in Rad50 or lacking CARD9 consequently exhibited defective DNA-induced production of IL-1β, and Card9(-/-) mice had impaired inflammatory responses after infection with a DNA virus in vivo. Our results define a cytosolic DNA-recognition pathway for inflammation and a physical and functional connection between a conserved DNA-damage sensor and the innate immune response to pathogens.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acid Anhydride Hydrolases
  • Adaptor Proteins, Signal Transducing / immunology
  • Animals
  • B-Cell CLL-Lymphoma 10 Protein
  • CARD Signaling Adaptor Proteins / genetics
  • CARD Signaling Adaptor Proteins / immunology*
  • Cell Line
  • Cytosol / immunology
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / immunology*
  • DNA, Viral / immunology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology*
  • Dendritic Cells / immunology
  • Enzyme Activation
  • Humans
  • Interleukin-1beta / biosynthesis*
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Mice
  • Mice, Knockout
  • NF-kappa B / immunology
  • Signal Transduction
  • Toll-Like Receptor 4 / biosynthesis
  • Toll-Like Receptor 9 / biosynthesis
  • Vaccinia virus / genetics
  • Vaccinia virus / immunology*

Substances

  • Adaptor Proteins, Signal Transducing
  • B-Cell CLL-Lymphoma 10 Protein
  • Bcl10 protein, mouse
  • CARD Signaling Adaptor Proteins
  • CARD9 protein, human
  • DNA, Viral
  • DNA-Binding Proteins
  • Interleukin-1beta
  • Membrane Proteins
  • NF-kappa B
  • Sting1 protein, mouse
  • Tlr4 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 4
  • Toll-Like Receptor 9
  • Acid Anhydride Hydrolases
  • RAD50 protein, human
  • DNA Repair Enzymes