A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA.
The innate immune system recognizes nucleic acids during infection or tissue damage; however, the mechanisms of intracellular recognition of DNA have not been fully elucidated. Here we show that intracellular administration of double-stranded B-form DNA (B-DNA) triggered antiviral responses including production of type I interferons and chemokines independently of Toll-like receptors or the helicase RIG-I. B-DNA activated transcription factor IRF3 and the promoter of the gene encoding interferon-beta through a signaling pathway that required the kinases TBK1 and IKKi, whereas there was substantial activation of transcription factor NF-kappaB independent of both TBK and IKKi. IPS-1, an adaptor molecule linking RIG-I and TBK1, was involved in B-DNA-induced activation of interferon-beta and NF-kappaB. B-DNA signaling by this pathway conferred resistance to viral infection in a way dependent on both TBK1 and IKKi. These results suggest that both TBK1 and IKKi are required for innate immune activation by B-DNA, which might be important in antiviral innate immunity and other DNA-associated immune disorders.
Ishii
Ken J
KJ
Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
Coban
Cevayir
C
Kato
Hiroki
H
Takahashi
Ken
K
Torii
Yuichi
Y
Takeshita
Fumihiko
F
Ludwig
Holger
H
Sutter
Gerd
G
Suzuki
Koichi
K
Hemmi
Hiroaki
H
Sato
Shintaro
S
Yamamoto
Masahiro
M
Uematsu
Satoshi
S
Kawai
Taro
T
Takeuchi
Osamu
O
Akira
Shizuo
S
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D018925:Chemokines / Q000378:metabolism; D004247:DNA / Q000276:immunology*; D004269:DNA, Bacterial / Q000276:immunology; D004279:DNA, Viral / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology*; D014162:Transfection; D014777:Virus Diseases / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; D004269:DNA, Bacterial; D004279:DNA, Viral; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C494233:Irf3 protein, mouse; C505371:MAVS protein, human; D016328:NF-kappa B; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D004247:DNA; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase