A selective contribution of the RIG-I-like receptor pathway to type I interferon responses activated by cytosolic DNA.
The activation of the innate immune responses by DNA exposed within the cytosol has gained much attention and, in this context, several cytosolic DNA sensors have been identified. However, previous studies revealed the operation of redundant and complex mechanisms and it still remains to be clarified how the DNA-mediated evocation of diverse innate immune responses can be achieved. Here we show that two RIG-I-like receptors (RLRs), RIG-I and MDA5, known as cytosolic RNA receptors, nonredundantly function as cytosolic DNA receptors that lead to the selective activation of type I IFN genes. We demonstrate that overexpression of otherwise IFN-inducible RIG-I or MDA5 in IFN signal-deficient cells results in a marked enhancement of type I IFN gene induction upon cytosolic DNA stimulation, while in their absence the induction is impaired. Interestingly, the DNA-mediated induction of other cytokine genes was barely affected by the absence of RLRs. Indeed, unlike the RNA-RLR pathway that activates the transcription factors IRF3 and NF-kappaB, the DNA-RLR pathway is primarily responsible for the IRF3 activation critical for type I IFN gene transcription, illustrating a deliberate divergence of the DNA signaling pathways. Expectedly, the RLR pathway also contributes to intricate innate immune responses against infection by a DNA virus. Our study may provide insights into the complexity of host defense mechanisms that thwart immune evasion by DNA-containing pathogens.
Choi
Myoung Kwon
MK
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Wang
ZhiChao
Z
Ban
Tatsuma
T
Yanai
Hideyuki
H
Lu
Yan
Y
Koshiba
Ryuji
R
Nakaima
Yukana
Y
Hangai
Sho
S
Savitsky
David
D
Nakasato
Makoto
M
Negishi
Hideo
H
Takeuchi
Osamu
O
Honda
Kenya
K
Akira
Shizuo
S
Tamura
Tomohiko
T
Taniguchi
Tadatsugu
T
D000818:Animals; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics* / Q000276:immunology*; D004267:DNA Viruses / Q000235:genetics / Q000276:immunology; D004279:DNA, Viral / Q000235:genetics / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007370:Interferon Type I / Q000235:genetics*; D000072640:Interferon-Induced Helicase, IFIH1; D051379:Mice; D018345:Mice, Knockout; D012313:RNA / Q000235:genetics / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
D004279:DNA, Viral; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta; D012313:RNA; D004247:DNA; C503356:Ddx58 protein, mouse; C510592:Ifih1 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1