title: A selective contribution of the RIG-I-like receptor pathway to type I interferon responses activated by cytosolic DNA.
abstract: 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.
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Myoung Kwon
authors.initials: MK
authors.lastname: Choi
authors.forename: ZhiChao
authors.initials: Z
authors.lastname: Wang
authors.forename: Tatsuma
authors.initials: T
authors.lastname: Ban
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yanai
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Ryuji
authors.initials: R
authors.lastname: Koshiba
authors.forename: Yukana
authors.initials: Y
authors.lastname: Nakaima
authors.forename: Sho
authors.initials: S
authors.lastname: Hangai
authors.forename: David
authors.initials: D
authors.lastname: Savitsky
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakasato
authors.forename: Hideo
authors.initials: H
authors.lastname: Negishi
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Tamura
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
mesh_terms: 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
chemical_list: 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