Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1β production.
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.
Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Susanne
S
Roth
Department Biology II and Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Martinsried, Germany.
Andrea
A
Rottach
Kinderklinik und Kinderpoliklinik im Dr. von Haunersches Kinderspital, Ludwig-Maximilians-Universität, Munich, Germany.
Amelie S
AS
Lotz-Havla
Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Verena
V
Laux
Institut für Virologie, Klinikum rechts der Isar, Technische Universität München, and Helmholtz Zentrum München, German Research Centre for Environmental Health, Munich, Germany.
Andreas
A
Muschaweckh
Kinderklinik und Kinderpoliklinik im Dr. von Haunersches Kinderspital, Ludwig-Maximilians-Universität, Munich, Germany.
Søren W
SW
Gersting
Kinderklinik und Kinderpoliklinik im Dr. von Haunersches Kinderspital, Ludwig-Maximilians-Universität, Munich, Germany.
Ania C
AC
Muntau
Department of Biochemistry, Gene Center and Center for integrated Protein Science Munich, Ludwig-Maximilians-Universität, Munich, Germany.
Karl-Peter
KP
Hopfner
Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
Lei
L
Jin
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Katelynd
K
Vanness
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
John H J
JH
Petrini
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.
Ingo
I
Drexler
Department Biology II and Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Martinsried, Germany.
Heinrich
H
Leonhardt
Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Jürgen
J
Ruland
D017766:Acid Anhydride Hydrolases; D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D003600:Cytosol / Q000276:immunology; D045643:DNA Repair Enzymes / Q000235:genetics / Q000276:immunology*; D004279:DNA, Viral / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D004789:Enzyme Activation; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis; D051217:Toll-Like Receptor 9 / Q000096:biosynthesis; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology*; D000099197:STING Protein
D017766:Acid Anhydride Hydrolases; D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins; D045643:DNA Repair Enzymes; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D053583:Interleukin-1beta; D008565:Membrane Proteins; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; C488088:Bcl10 protein, mouse; C505855:CARD9 protein, human; C530855:Sting1 protein, mouse; D000099197:STING Protein; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; C112158:RAD50 protein, human