Journal
NATURE IMMUNOLOGY
Volume 15, Issue 6, Pages 538-545Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.2888
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Funding
- Bavarian Genome Research Network
- Ludwig-Maximilians-Universitat Excellence Initiative [42595-6]
- Deutsche Forschungsgemeinschaft [SFB684, SFB1054]
- US National Institutes of Health [U19A1083025, GM56888]
- European Research Council
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Double-stranded DNA (dsDNA) in the cytoplasm triggers the production of interleukin 1 beta (IL-1 beta) 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-kappa B and the generation of pro-IL-1 beta. Primary cells conditionally deficient in Rad50 or lacking CARD9 consequently exhibited defective DNA-induced production of IL-1 beta, 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.
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