A selective contribution of the RIG-I-like receptor pathway to type I interferon responses activated by cytosolic DNA

Kwon Choi Myoung, Zhichao Wang, Tatsuma Ban, Hideyuki Yanai, Yan Lu, Ryuji Koshiba, Yukana Nakaima, Sho Hangai, David Savitsky, Makoto Nakasato, Hideo Negishi, Osamu Takeuchi, Kenya Honda, Shizuo Akira, Tomohiko Tamura, Tadatsugu Taniguchi

Research output: Contribution to journalArticle

74 Citations (Scopus)

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-κB, 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.

Original languageEnglish
Pages (from-to)17870-17875
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number42
DOIs
Publication statusPublished - 2009 Oct 20

Keywords

  • DNA sensor
  • IRF3
  • Innate immunity
  • NF-κB

ASJC Scopus subject areas

  • General

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    Myoung, K. C., Wang, Z., Ban, T., Yanai, H., Lu, Y., Koshiba, R., Nakaima, Y., Hangai, S., Savitsky, D., Nakasato, M., Negishi, H., Takeuchi, O., Honda, K., Akira, S., Tamura, T., & Taniguchi, T. (2009). A selective contribution of the RIG-I-like receptor pathway to type I interferon responses activated by cytosolic DNA. Proceedings of the National Academy of Sciences of the United States of America, 106(42), 17870-17875. https://doi.org/10.1073/pnas.0909545106