Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction

Nature Immunology volume 6, pages 981–988 (2005)Cite this article

Abstract

Type I interferons are central mediators for antiviral responses. Using high-throughput functional screening of interferon inducers, we have identified here a molecule we call interferon-β promoter stimulator 1 (IPS-1). Overexpression of IPS-1 induced type I interferon and interferon-inducible genes through activation of IRF3, IRF7 and NF-κB transcription factors. TBK1 and IKKi protein kinases were required for the IPS-1-mediated interferon induction. IPS-1 contained an N-terminal CARD-like structure that mediated interaction with the CARD of RIG-I and Mda5, which are cytoplasmic RNA helicases that sense viral infection. 'Knockdown' of IPS-1 by small interfering RNA blocked interferon induction by virus infection. Thus, IPS-1 is an adaptor involved in RIG-I- and Mda5-mediated antiviral immune responses.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structure and expression of IPS-1.
Figure 2: Activation of type I interferon promoters by IPS-1.
Figure 3: IPS-1 induces antiviral responses.
Figure 4: NF-κB activation and IL-8 induction by IPS-1.
Figure 5: IPS-1 associates with RIG-I, Mda5, FADD and RIP1.
Figure 6: Knockdown of IPS-1 expression by siRNA.

Similar content being viewed by others

Accession codes

Accessions

BINDPlus

References

  1. Janeway, C.A. Jr. & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

    Article  CAS  Google Scholar 

  2. Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).

    Article  CAS  Google Scholar 

  3. Akira, S. & Takeda, K. Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499–511 (2004).

    Article  CAS  Google Scholar 

  4. Alexopoulou, L., Holt, A.C., Medzhitov, R. & Flavell, R.A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001).

    Article  CAS  Google Scholar 

  5. Yamamoto, M. et al. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-β promoter in the Toll-like receptor signaling. J. Immunol. 169, 6668–6672 (2002).

    Article  CAS  Google Scholar 

  6. Oshiumi, H., Matsumoto, M., Funami, K., Akazawa, T. & Seya, T. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-β induction. Nat. Immunol. 4, 161–167 (2003).

    Article  CAS  Google Scholar 

  7. Sharma, S. et al. Triggering the interferon antiviral response through an IKK-related pathway. Science 300, 1148–1151 (2003).

    Article  CAS  Google Scholar 

  8. Fitzgerald, K.A. et al. IKKε and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol. 4, 491–496 (2003).

    Article  CAS  Google Scholar 

  9. Sato, S. et al. Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-κB and IFN-regulatory factor-3, in the Toll-like receptor signaling. J. Immunol. 171, 4304–4310 (2003).

    Article  CAS  Google Scholar 

  10. Meylan, E. et al. RIP1 is an essential mediator of Toll-like receptor 3-induced NF-κB activation. Nat. Immunol. 5, 503–507 (2004).

    Article  CAS  Google Scholar 

  11. Heil, F. et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303, 1526–1529 (2004).

    Article  CAS  Google Scholar 

  12. Diebold, S.S. et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004).

    Article  CAS  Google Scholar 

  13. Hemmi, H., Kaisho, T., Takeda, K. & Akira, S. The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J. Immunol. 170, 3059–3064 (2003).

    Article  CAS  Google Scholar 

  14. Hoshino, K., Kaisho, T., Iwabe, T., Takeuchi, O. & Akira, S. Differential involvement of IFN-β in Toll-like receptor-stimulated dendritic cell activation. Int. Immunol. 14, 1225–1231 (2002).

    Article  CAS  Google Scholar 

  15. Kawai, T. et al. Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat. Immunol. 5, 1061–1068 (2004).

    Article  CAS  Google Scholar 

  16. Honda, K. et al. Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc. Natl. Acad. Sci. USA 101, 15416–15421 (2004).

    Article  CAS  Google Scholar 

  17. Uematsu, S. et al. Interleukin-1 receptor-associated kinase-1 (IRAK-1) plays an essential role for TLR7- and TLR9-mediated interferon-α induction. J. Exp. Med. 201, 915–923 (2005).

    Article  CAS  Google Scholar 

  18. Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640–643 (2003).

    Article  CAS  Google Scholar 

  19. Hoebe, K. et al. Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways. Nat. Immunol. 4, 1223–1229 (2003).

    Article  CAS  Google Scholar 

  20. Hemmi, H. et al. The roles of two IκB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J. Exp. Med. 199, 1641–1650 (2004).

    Article  CAS  Google Scholar 

  21. Perry, A.K., Chow, E.K., Goodnough, J.B., Yeh, W.C. & Cheng, G. Differential requirement for TANK-binding kinase-1 in type I interferon responses to Toll-like receptor activation and viral infection. J. Exp. Med. 199, 1651–1658 (2004).

    Article  CAS  Google Scholar 

  22. McWhirter, S.M. et al. IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts. Proc. Natl. Acad. Sci. USA 101, 233–238 (2004).

    Article  CAS  Google Scholar 

  23. Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5, 730–737 (2004).

    Article  CAS  Google Scholar 

  24. Kato, H. et al. Cell type specific involvement of RIG-I in antiviral response. Immunity 23, 19–28 (2005).

    Article  CAS  Google Scholar 

  25. Kovacsovics, M. et al. Overexpression of Helicard, a CARD-containing helicase cleaved during apoptosis, accelerates DNA degradation. Curr. Biol. 12, 838–843 (2002).

    Article  CAS  Google Scholar 

  26. Andrejeva, J. et al. The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter. Proc. Natl. Acad. Sci. USA 101, 17264–17269 (2004).

    Article  CAS  Google Scholar 

  27. Balachandran, S., Thomas, E. & Barber, G.N. A FADD-dependent innate immune mechanism in mammalian cells. Nature 432, 401–405 (2004).

    Article  CAS  Google Scholar 

  28. Matsuda, A. et al. Large-scale identification and characterization of human genes that activate NF-κB and MAPK signaling pathways. Oncogene 22, 3307–3318 (2003).

    Article  CAS  Google Scholar 

  29. Jayakar, H.R. & Whitt, M.A. Identification of two additional translation products from the matrix (M) gene that contribute to vesicular stomatitis virus cytopathology. J. Virol. 76, 8011–8018 (2002).

    Article  CAS  Google Scholar 

  30. Pomerantz, J.L. & Baltimore, D. NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase. EMBO J. 18, 6694–6704 (1999).

    Article  CAS  Google Scholar 

  31. Nomura, F., Kawai, T., Nakanishi, K. & Akira, S. NF-κB activation through IKK-i-dependent I-TRAF/TANK phosphorylation. Genes Cells 5, 191–202 (2000).

    Article  CAS  Google Scholar 

  32. Sasai, M. et al. NF-κB-activating kinase-associated protein 1 participates in TLR3/Toll-IL-1 homology domain-containing adapter molecule-1-mediated IFN regulatory factor 3 activation. J. Immunol. 174, 27–30 (2005).

    Article  CAS  Google Scholar 

  33. Sumpter, R. Jr. et al. Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J. Virol. 79, 2689–2699 (2005).

    Article  CAS  Google Scholar 

  34. Breiman, A. et al. Inhibition of RIG-I-dependent signaling to the interferon pathway during hepatitis C virus expression and restoration of signaling by IKKε. J. Virol. 79, 3969–3978 (2005).

    Article  CAS  Google Scholar 

  35. Stockinger, S. et al. IFN regulatory factor 3-dependent induction of type I IFNs by intracellular bacteria is mediated by a TLR- and Nod2-independent mechanism. J. Immunol. 173, 7416–7425 (2004).

    Article  CAS  Google Scholar 

  36. O'Connell, R.M. et al. Immune activation of type I IFNs by Listeria monocytogenes occurs independently of TLR4, TLR2, and receptor interacting protein 2 but involves TNFR-associated NF-κB kinase-binding kinase 1. J. Immunol. 174, 1602–1607 (2005).

    Article  CAS  Google Scholar 

  37. Pomerantz, J.L., Denny, E.M. & Baltimore, D. CARD11 mediates factor-specific activation of NF-κB by the T cell receptor complex. EMBO J. 21, 5184–5194 (2002).

    Article  CAS  Google Scholar 

  38. Sugiyama, T. et al. CpG RNA: identification of novel single-stranded RNA that stimulates human CD14+CD11c+ monocytes. J. Immunol. 174, 2273–2279 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J.L. Pomerantz and T. Miyazaki for suggestions; D.T. Golenbock for plasmids; T. Abe, Y. Matsuura and T. Fujita for viruses; S. Uematsu, M. Yamamoto and Y. Torii for discussions; A. Miyabe, and A. Shibano for technical support; and M. Hashimoto for secretarial assistance.

Author information

Authors and Affiliations

  1. Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan

    Taro Kawai, Shintaro Sato, Ken J Ishii, Osamu Takeuchi & Shizuo Akira

  2. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan

    Ken Takahashi, Himanshu Kumar, Hiroki Kato, Osamu Takeuchi & Shizuo Akira

  3. The 21st Century COE, Combined Program on Microbiology and Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan

    Cevayir Coban & Shizuo Akira

  4. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Sakyoku, Kyoto, 606-8507, Japan

    Ken Takahashi

Authors
  1. Taro Kawai
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Ken Takahashi
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Shintaro Sato
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Cevayir Coban
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Himanshu Kumar
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Hiroki Kato
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Ken J Ishii
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Osamu Takeuchi
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Shizuo Akira
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Shizuo Akira.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Identification of activators for IFN-β promoter. (PDF 59 kb)

Supplementary Table 1

Summary of isolates. (PDF 7 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kawai, T., Takahashi, K., Sato, S. et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 6, 981–988 (2005). https://doi.org/10.1038/ni1243

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1243

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing