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

ABSTRACT: Double-stranded DNA (dsDNA) in the cytoplasm triggers the production of interleukin 1? (IL-1?) 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-?B and the generation of pro-IL-1?. Primary cells conditionally deficient in Rad50 or lacking CARD9 consequently exhibited defective DNA-induced production of IL-1?, 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.

SUBMITTER: Roth S 

PROVIDER: S-EPMC4309842 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature