Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1β production
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Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1β production. / Roth, Susanne; Rottach, Andrea; Lotz-Havla, Amelie S; Laux, Verena; Muschaweckh, Andreas; Gersting, Søren W; Muntau, Ania C; Hopfner, Karl-Peter; Jin, Lei; Vanness, Katelynd; Petrini, John H J; Drexler, Ingo; Leonhardt, Heinrich; Ruland, Jürgen.
in: NAT IMMUNOL, Jahrgang 15, Nr. 6, 01.06.2014, S. 538-45.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1β production
AU - Roth, Susanne
AU - Rottach, Andrea
AU - Lotz-Havla, Amelie S
AU - Laux, Verena
AU - Muschaweckh, Andreas
AU - Gersting, Søren W
AU - Muntau, Ania C
AU - Hopfner, Karl-Peter
AU - Jin, Lei
AU - Vanness, Katelynd
AU - Petrini, John H J
AU - Drexler, Ingo
AU - Leonhardt, Heinrich
AU - Ruland, Jürgen
PY - 2014/6/1
Y1 - 2014/6/1
N2 - 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.
AB - 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.
KW - Adaptor Proteins, Signal Transducing
KW - Animals
KW - CARD Signaling Adaptor Proteins
KW - Cell Line
KW - Cytosol
KW - DNA Repair Enzymes
KW - DNA, Viral
KW - DNA-Binding Proteins
KW - Dendritic Cells
KW - Enzyme Activation
KW - Humans
KW - Interleukin-1beta
KW - Membrane Proteins
KW - Mice
KW - Mice, Knockout
KW - NF-kappa B
KW - Signal Transduction
KW - Toll-Like Receptor 4
KW - Toll-Like Receptor 9
KW - Vaccinia virus
U2 - 10.1038/ni.2888
DO - 10.1038/ni.2888
M3 - SCORING: Journal article
C2 - 24777530
VL - 15
SP - 538
EP - 545
JO - NAT IMMUNOL
JF - NAT IMMUNOL
SN - 1529-2908
IS - 6
ER -