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

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

Author information

1
Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
2
Department Biology II and Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Martinsried, Germany.
3
Kinderklinik und Kinderpoliklinik im Dr. von Haunersches Kinderspital, Ludwig-Maximilians-Universität, Munich, Germany.
4
Institut für Virologie, Klinikum rechts der Isar, Technische Universität München, and Helmholtz Zentrum München, German Research Centre for Environmental Health, Munich, Germany.
5
Department of Biochemistry, Gene Center and Center for integrated Protein Science Munich, Ludwig-Maximilians-Universität, Munich, Germany.
6
Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
7
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
8
1] Institut für Virologie, Klinikum rechts der Isar, Technische Universität München, and Helmholtz Zentrum München, German Research Centre for Environmental Health, Munich, Germany. [2] Institut für Virologie, Universitätsklinikum Düsseldorf, Heinrich Heine Universität, Düsseldorf, Germany.

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.

PMID:
24777530
PMCID:
PMC4309842
DOI:
10.1038/ni.2888
[Indexed for MEDLINE]
Free PMC Article

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