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:

Akirins are highly conserved nuclear proteins required for NF-κB-dependent gene expression in drosophila and mice

Nature Immunology volume 9, pages 97–104 (2008)Cite this article

A Corrigendum to this article was published on 01 February 2008

This article has been updated

Abstract

During a genome-wide screen with RNA-mediated interference, we isolated CG8580 as a gene involved in the innate immune response of Drosophila melanogaster. CG8580, which we called Akirin, encoded a protein that acted in parallel with the NF-κB transcription factor downstream of the Imd pathway and was required for defense against Gram-negative bacteria. Akirin is highly conserved, and the human genome contains two homologs, one of which was able to rescue the loss-of-function phenotype in drosophila cells. Akirins were strictly localized to the nucleus. Knockout of both Akirin homologs in mice showed that one had an essential function downstream of the Toll-like receptor, tumor necrosis factor and interleukin (IL)-1β signaling pathways leading to the production of IL-6. Thus, Akirin is a conserved nuclear factor required for innate immune responses.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Unrooted evolutionary tree of Akirin homologs: Akirins are highly conserved.
Figure 2: Nuclear localization of Akirins.
Figure 3: Effect of RNAi knock-down of drosophila Akirin on the activation of the Imd and Toll pathways in drosophila S2 cells.
Figure 4: Epistatic analysis of D. melanogaster Akirin position within the Imd pathway.
Figure 5: In vivo function of D. melanogaster Akirin.
Figure 6: TLR-, IL-1β- and TNF-induced IL-6 production in Akirin1−/− and Akirin2−/− mouse embryonic fibroblasts (MEFs).
Figure 7: LPS- and IL-1β-induced gene expression in Akirin2−/− MEFs.
Figure 8: LPS- and IL-1β-induced activation of NF-κB in Akirin2−/− MEFs.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

Change history

  • 11 January 2008

    In the version of this article initially published, the bars for the LPS samples in Figure 6b are incorrect. The correct data are presented here.

  • 11 December 2009

    In addition, an incorrect accession code was given for Xenopus laevis Akirin1; the correct code is NP_001089245. These errors have been corrected in the HTML and PDF versions of the article.

References

  1. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).

    Article  CAS  Google Scholar 

  2. Brennan, C.A. & Anderson, K.V. Drosophila: the genetics of innate immune recognition and response. Annu. Rev. Immunol. 22, 457–483 (2004).

    Article  CAS  Google Scholar 

  3. Hoffmann, J.A. The immune response of Drosophila. Nature 426, 33–38 (2003).

    Article  CAS  Google Scholar 

  4. Lemaitre, B. & Hoffmann, J. The host defense of Drosophila melanogaster. Annu. Rev. Immunol. 25, 697–743 (2007).

    Article  CAS  Google Scholar 

  5. Hoffmann, J.A. & Reichhart, J.M. Drosophila innate immunity: an evolutionary perspective. Nat. Immunol. 3, 121–126 (2002).

    Article  CAS  Google Scholar 

  6. Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J.M. & Hoffmann, J.A. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973–983 (1996).

    Article  CAS  Google Scholar 

  7. Weber, A.N. et al. Binding of the Drosophila cytokine Spatzle to Toll is direct and establishes signaling. Nat. Immunol. 4, 794–800 (2003).

    Article  CAS  Google Scholar 

  8. Ip, Y. et al. Dif, a dorsal-related gene that mediates an immune response in Drosophila. Cell 75, 753–763 (1993).

    Article  CAS  Google Scholar 

  9. Rutschmann, S. et al. The Rel protein DIF mediates the antifungal but not the antibacterial host defense in Drosophila. Immunity 12, 569–580 (2000).

    Article  CAS  Google Scholar 

  10. Tauszig-Delamasure, S., Bilak, H., Capovilla, M., Hoffmann, J.A. & Imler, J.L. Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections. Nat. Immunol. 3, 91–97 (2002).

    Article  CAS  Google Scholar 

  11. Stoven, S. et al. Caspase-mediated processing of the Drosophila NF-κB factor Relish. Proc. Natl. Acad. Sci. USA 100, 5991–5996 (2003).

    Article  CAS  Google Scholar 

  12. Silverman, N. et al. A Drosophila IκB kinase complex required for Relish cleavage and antibacterial immunity. Genes Dev. 14, 2461–2471 (2000).

    Article  CAS  Google Scholar 

  13. Dushay, M.S., Asling, B. & Hultmark, D. Origins of immunity: Relish, a compound Rel-like gene in the antibacterial defense of Drosophila. Proc. Natl. Acad. Sci. USA 93, 10343–10347 (1996).

    Article  CAS  Google Scholar 

  14. Mak, T.W. & Yeh, W.C. Signaling for survival and apoptosis in the immune system. Arthritis Res. 4, S243–S252 (2002).

    Article  Google Scholar 

  15. Choe, K.M., Werner, T., Stoven, S., Hultmark, D. & Anderson, K.V. Requirement for a peptidoglycan recognition protein (PGRP) in Relish activation and antibacterial immune responses in Drosophila. Science 296, 359–362 (2002).

    Article  CAS  Google Scholar 

  16. Gottar, M. et al. The Drosophila immune response against Gram-negative bacteria is mediated by a peptidoglycan recognition protein. Nature 416, 640–644 (2002).

    Article  CAS  Google Scholar 

  17. Leulier, F. et al. The Drosophila immune system detects bacteria through specific peptidoglycan recognition. Nat. Immunol. 4, 478–484 (2003).

    Article  CAS  Google Scholar 

  18. Kaneko, T. et al. Monomeric and polymeric gram-negative peptidoglycan but not purified LPS stimulate the Drosophila IMD pathway. Immunity 20, 637–649 (2004).

    Article  CAS  Google Scholar 

  19. Mellroth, P. et al. Ligand-induced dimerization of Drosophila peptidoglycan recognition proteins in vitro. Proc. Natl. Acad. Sci. USA 102, 6455–6460 (2005).

    Article  CAS  Google Scholar 

  20. Takehana, A. et al. Overexpression of a pattern-recognition receptor, peptidoglycan-recognition protein-LE, activates imd/relish-mediated antibacterial defense and the prophenoloxidase cascade in Drosophila larvae. Proc. Natl. Acad. Sci. USA 99, 13705–13710 (2002).

    Article  CAS  Google Scholar 

  21. Choe, K.M., Lee, H. & Anderson, K.V. Drosophila peptidoglycan recognition protein LC (PGRP-LC) acts as a signal-transducing innate immune receptor. Proc. Natl. Acad. Sci. USA 102, 1122–1126 (2005).

    Article  CAS  Google Scholar 

  22. Georgel, P. et al. Drosophila immune deficiency (IMD) is a death domain protein that activates antibacterial defense and can promote apoptosis. Dev. Cell 1, 503–514 (2001).

    Article  CAS  Google Scholar 

  23. Kelliher, M.A. et al. The death domain kinase RIP mediates the TNF-induced NF-κB signal. Immunity 8, 297–303 (1998).

    Article  CAS  Google Scholar 

  24. Leulier, F., Rodriguez, A., Khush, R.S., Abrams, J.M. & Lemaitre, B. The Drosophila caspase Dredd is required to resist gram-negative bacterial infection. EMBO Rep. 1, 353–358 (2000).

    Article  CAS  Google Scholar 

  25. Naitza, S. et al. The Drosophila immune defense against gram-negative infection requires the death protein dFADD. Immunity 17, 575–581 (2002).

    Article  CAS  Google Scholar 

  26. Zhuang, Z.H. et al. Drosophila TAB2 is required for the immune activation of JNK and NF-κB. Cell. Signal. 18, 964–970 (2006).

    Article  CAS  Google Scholar 

  27. Gesellchen, V., Kuttenkeuler, D., Steckel, M., Pelte, N. & Boutros, M. An RNA interference screen identifies Inhibitor of Apoptosis Protein 2 as a regulator of innate immune signalling in Drosophila. EMBO Rep. 6, 979–984 (2005).

    Article  CAS  Google Scholar 

  28. Vidal, S. et al. Mutations in the Drosophila dTAK1 gene reveal a conserved function for MAPKKKs in the control of rel/NF-κB-dependent innate immune responses. Genes Dev. 15, 1900–1912 (2001).

    Article  CAS  Google Scholar 

  29. Rutschmann, S. et al. Role of Drosophila IKKγ in a toll-independent antibacterial immune response. Nat. Immunol. 1, 342–347 (2000).

    Article  CAS  Google Scholar 

  30. Lu, Y., Wu, L.P. & Anderson, K.V. The antibacterial arm of the Drosophila innate immune response requires an IκB kinase. Genes Dev. 15, 104–110 (2001).

    Article  CAS  Google Scholar 

  31. Deng, L. et al. Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103, 351–361 (2000).

    Article  CAS  Google Scholar 

  32. Wang, C. et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346–351 (2001).

    Article  CAS  Google Scholar 

  33. Boutros, M. et al. Genome-wide RNAi analysis of growth and viability in Drosophila cells. Science 303, 832–835 (2004).

    Article  CAS  Google Scholar 

  34. Crosby, M.A., Goodman, J.L., Strelets, V.B., Zhang, P. & Gelbart, W.M. FlyBase: genomes by the dozen. Nucleic Acids Res. 35, D486–D491 (2007).

    Article  CAS  Google Scholar 

  35. Reichhart, J.M. et al. Splice-activated UAS hairpin vector gives complete RNAi knockout of single or double target transcripts in Drosophila melanogaster. Genesis 34, 160–164 (2002).

    Article  CAS  Google Scholar 

  36. Pena-Rangel, M.T., Rodriguez, I. & Riesgo-Escovar, J.R. A misexpression study examining dorsal thorax formation in Drosophila melanogaster. Genetics 160, 1035–1050 (2002).

    PubMed  PubMed Central  Google Scholar 

  37. DasGupta, R., Kaykas, A., Moon, R.T. & Perrimon, N. Functional genomic analysis of the Wnt-wingless signaling pathway. Science 308, 826–833 (2005).

    Article  CAS  Google Scholar 

  38. Blumenthal, A. et al. The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation. Blood 108, 965–973 (2006).

    Article  CAS  Google Scholar 

  39. Gross, I., Georgel, P., Kappler, C., Reichhart, J.M. & Hoffmann, J.A. Drosophila immunity: a comparative analysis of the Rel proteins dorsal and Dif in the induction of the genes encoding diptericin and cecropin. Nucleic Acids Res. 24, 1238–1245 (1996).

    Article  CAS  Google Scholar 

  40. Combet, C., Blanchet, C., Geourjon, C. & Deleage, G. NPS@: network protein sequence analysis. Trends Biochem. Sci. 25, 147–150 (2000).

    Article  CAS  Google Scholar 

  41. Kumar, S., Tamura, K. & Nei, M. MEGA3: integrated software for molecular evolutionary genetics analysis and sequence alignment. Brief. Bioinform. 5, 150–163 (2004).

    Article  CAS  Google Scholar 

  42. Leclerc, V. et al. Prophenoloxidase activation is not required for survival to microbial infections in Drosophila. EMBO Rep. 7, 231–235 (2006).

    Article  CAS  Google Scholar 

  43. Ligoxygakis, P., Pelte, N., Hoffmann, J.A. & Reichhart, J.M. Activation of Drosophila Toll during fungal infection by a blood serine protease. Science 297, 114–116 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Stöven for Relish constructs; J.L. Imler for reporter constructs; S. Kurata for support to A.G. and discussions; M. Shiokawa, Y. Fujiwara, L. Troxler, A. Meunier and R. Walther for technical help; M. Hashimoto for secretarial assistance; and our colleagues for discussions and suggestions. Supported by the Japan Society for the Promotion of Science (A.G.), the Centre National de la Recherche Scientifique, the Ministère de l'Education Nationale de la Recherche et de la Technologie, Special Coordination Funds, the Japanese Ministry of Education, Culture, Sports, Science and Technology, the US National Institutes of Health (AI070167 and AI44220) and the Emmy-Noether Program of the Deutsche Forschungsgemeinschaft.

Author information

Author notes

  1. Akira Goto

    Present address: Present address: Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki Aoba-ku, Sendai, 980-8578, Japan.,

  2. Akira Goto and Kazufumi Matsushita: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut de Biologie Moléculaire et Cellulaire, CNRS UPR 9022, Université Louis Pasteur, Strasbourg, 67084, Cedex, France

    Akira Goto, Laure El Chamy, Jules A Hoffmann & Jean-Marc Reichhart

  2. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, ERATO, Japan Science and Technology Agency, 3-1 Yamada-oka, Suita, 565-0871, Osaka, Japan

    Kazufumi Matsushita, Osamu Takeuchi & Shizuo Akira

  3. German Cancer Research Center (DKFZ), Boveri-Group Signaling and Functional Genomics, Heidelberg, D-69120, Germany

    Viola Gesellchen, David Kuttenkeuler & Michael Boutros

Authors
  1. Akira Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazufumi Matsushita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Viola Gesellchen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laure El Chamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Kuttenkeuler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Osamu Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jules A Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shizuo Akira
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael Boutros
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jean-Marc Reichhart
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.G., V.G., L.E.C. and D.K. did the drosophila experiments. K.M. and O.T. did the mouse experiments. S.A., M.B., O.T. and J.-M.R. conceived and directed the experiments. A.G., O.T., J.A.H. and J.-M.R. wrote the paper. All authors contributed to manuscript criticism.

Corresponding author

Correspondence to Jean-Marc Reichhart.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Table 1 and Methods (PDF 434 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goto, A., Matsushita, K., Gesellchen, V. et al. Akirins are highly conserved nuclear proteins required for NF-κB-dependent gene expression in drosophila and mice. Nat Immunol 9, 97–104 (2008). https://doi.org/10.1038/ni1543

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1543

This article is cited by

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