Skip to main content
SpringerLink
Log in

Evolution of Vertebrate Immunity: Sequence and Functional Analysis of the SEFIR Domain Family Member Act1

  • Published:
Journal of Molecular Evolution Aims and scope Submit manuscript

Abstract

SEF/IL-17R/CIKS/ACT1 homology (SEFIR) domain containing proteins, which include the IL-17 receptors and an adaptor protein Act1, have essential roles in vertebrate immunity. However, the molecular mechanisms of Act1 function remain largely unexplored. In this article, we employed an evolutionary analysis to discover novel structural and functional properties of Act1. Firstly, we have found that the previously identified helix-loop-helix and Ufd2-box domains in human Act1 have relatively recent evolutionary origins in higher vertebrates. Zebrafish Act1, which lacks these domains, is unable to induce JNK phosphorylation and activate cytokine expression when expressed in human cells. Secondly, we have established that Act1-like proteins contain DEATH-domains in basal animals, such as Hydra and primitive chordates, but lack this domain in vertebrates. Finally, we have shown that Act1-TRAF6 interactions are conserved throughout vertebrate evolution: Act1 derived from zebrafish can bind to TRAF6 and activate NF-κB in human cells. Moreover, we have identified a novel highly conserved motif at the amino-terminus of Act1, which is critical for binding to TRAF6 and activating NF-κB-dependent gene expression. We propose a model of evolutionary changes in Act1-mediated signalling, which contributes to a better understanding of evolution of the vertebrate immunity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Aravind L, Koonin EV (2000) The U box is a modified RING finger—a common domain in ubiquitination. Curr Biol 10:R132–R134

    Article  PubMed  CAS  Google Scholar 

  • Bloor S, Ryzhakov G, Wagner S, Butler PJ, Smith DL, Krumbach R, Dikic I, Randow F (2008) Signal processing by its coil zipper domain activates IKK gamma. Proc Natl Acad Sci USA 105:1279–1284

    Article  PubMed  CAS  Google Scholar 

  • Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV (1996) TRAF6 is a signal transducer for interleukin-1. Nature 383:443–446

    Article  PubMed  CAS  Google Scholar 

  • Chang SH, Park H, Dong C (2006) Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. J Biol Chem 281:35603–35607

    Article  PubMed  CAS  Google Scholar 

  • Chen ZJ (2005) Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 7:758–765

    Article  PubMed  CAS  Google Scholar 

  • Dunn CW, Hejnol A, Matus DQ, Pang K, Browne WE, Smith SA, Seaver E, Rouse GW, Obst M, Edgecombe GD, Sorensen MV, Haddock SH, Schmidt-Rhaesa A, Okusu A, Kristensen RM, Wheeler WC, Martindale MQ, Giribet G (2008) Broad phylogenomic sampling improves resolution of the animal tree of life. Nature 452:745–749

    Article  PubMed  CAS  Google Scholar 

  • Gaffen SL (2009) Structure and signalling in the IL-17 receptor family. Nat Rev Immunol 9:556–567

    Article  PubMed  CAS  Google Scholar 

  • Huang F, Kao CY, Wachi S, Thai P, Ryu J, Wu R (2007) Requirement for both JAK-mediated PI3K signaling and ACT1/TRAF6/TAK1-dependent NF-kappaB activation by IL-17A in enhancing cytokine expression in human airway epithelial cells. J Immunol 179:6504–6513

    PubMed  CAS  Google Scholar 

  • Huffmeier U, Uebe S, Ekici AB, Bowes J, Giardina E, Korendowych E, Juneblad K, Apel M, McManus R, Ho P, Bruce IN, Ryan AW, Behrens F, Lascorz J, Bohm B, Traupe H, Lohmann J, Gieger C, Wichmann HE, Herold C, Steffens M, Klareskog L, Wienker TF, Fitzgerald O, Alenius GM, McHugh NJ, Novelli G, Burkhardt H, Barton A, Reis A (2010) Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nat Genet 42:996–999

    Article  PubMed  Google Scholar 

  • Huson DH, Richter DC, Rausch C, Dezulian T, Franz M, Rupp R (2007) Dendroscope: an interactive viewer for large phylogenetic trees. BMC Bioinform 8:460

    Article  Google Scholar 

  • Jiang J, Ballinger CA, Wu Y, Dai Q, Cyr DM, Hohfeld J, Patterson C (2001) CHIP is a U-box-dependent E3 ubiquitin ligase: identification of Hsc70 as a target for ubiquitylation. J Biol Chem 276:42938–42944

    Article  PubMed  CAS  Google Scholar 

  • Jiang Z, Zamanian-Daryoush M, Nie H, Silva AM, Williams BR, Li X (2003) Poly(I-C)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFkappa B and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB 2-PKR. J Biol Chem 278:16713–16719

    Article  PubMed  CAS  Google Scholar 

  • Kanamori M, Kai C, Hayashizaki Y, Suzuki H (2002) NF-kappaB activator Act1 associates with IL-1/Toll pathway adaptor molecule TRAF6. FEBS Lett 532:241–246

    Article  PubMed  CAS  Google Scholar 

  • King N, Westbrook MJ, Young SL, Kuo A, Abedin M, Chapman J, Fairclough S, Hellsten U, Isogai Y, Letunic I, Marr M, Pincus D, Putnam N, Rokas A, Wright KJ, Zuzow R, Dirks W, Good M, Goodstein D, Lemons D, Li W, Lyons JB, Morris A, Nichols S, Richter DJ, Salamov A, Sequencing JG, Bork P, Lim WA, Manning G, Miller WT, McGinnis W, Shapiro H, Tjian R, Grigoriev IV, Rokhsar D (2008) The genome of the choanoflagellate Monosiga brevicollis and the origin of metazoans. Nature 451:783–788

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi T, Walsh MC, Choi Y (2004) The role of TRAF6 in signal transduction and the immune response. Microbes Infect 6:1333–1338

    Article  PubMed  CAS  Google Scholar 

  • Leonardi A, Chariot A, Claudio E, Cunningham K, Siebenlist U (2000) CIKS, a connection to Ikappa B kinase and stress-activated protein kinase. Proc Natl Acad Sci USA 97:10494–10499

    Article  PubMed  CAS  Google Scholar 

  • Li X (2008) Act1 modulates autoimmunity through its dual functions in CD40L/BAFF and IL-17 signaling. Cytokine 41:105–113

    Article  PubMed  CAS  Google Scholar 

  • Li X, Commane M, Nie H, Hua X, Chatterjee-Kishore M, Wald D, Haag M, Stark GR (2000) Act1, an NF-kappa B-activating protein. Proc Natl Acad Sci USA 97:10489–10493

    Article  PubMed  CAS  Google Scholar 

  • Liu C, Qian W, Qian Y, Giltiay NV, Lu Y, Swaidani S, Misra S, Deng L, Chen ZJ, Li X (2009) Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. Sci Signal 2:ra63

    Google Scholar 

  • Muroi M, Tanamoto K (2008) TRAF6 distinctively mediates MyD88- and IRAK-1-induced activation of NF-kappaB. J Leukoc Biol 83:702–707

    Article  PubMed  CAS  Google Scholar 

  • Newman RM, Salunkhe P, Godzik A, Reed JC (2006) Identification and characterization of a novel bacterial virulence factor that shares homology with mammalian Toll/interleukin-1 receptor family proteins. Infect Immun 74:594–601

    Article  PubMed  CAS  Google Scholar 

  • Novatchkova M, Leibbrandt A, Werzowa J, Neubuser A, Eisenhaber F (2003) The STIR-domain superfamily in signal transduction, development and immunity. Trends Biochem Sci 28:226–229

    Article  PubMed  CAS  Google Scholar 

  • Pires N, Dolan L (2010) Origin and diversification of basic-helix-loop-helix proteins in plants. Mol Biol Evol 27:862–874

    Article  PubMed  CAS  Google Scholar 

  • Qian Y, Liu C, Hartupee J, Altuntas CZ, Gulen MF, Jane-Wit D, Xiao J, Lu Y, Giltiay N, Liu J, Kordula T, Zhang QW, Vallance B, Swaidani S, Aronica M, Tuohy VK, Hamilton T, Li X (2007) The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol 8:247–256

    Article  PubMed  CAS  Google Scholar 

  • Santos CL, Tavares F, Thioulouse J, Normand P (2009) A phylogenomic analysis of bacterial helix-turn-helix transcription factors. FEMS Microbiol Rev 33:411–429

    Article  PubMed  CAS  Google Scholar 

  • Sasai M, Tatematsu M, Oshiumi H, Funami K, Matsumoto M, Hatakeyama S, Seya T (2010) Direct binding of TRAF2 and TRAF6 to TICAM-1/TRIF adaptor participates in activation of the Toll-like receptor 3/4 pathway. Mol Immunol 47:1283–1291

    Article  PubMed  CAS  Google Scholar 

  • Schwandner R, Yamaguchi K, Cao Z (2000) Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J Exp Med 191:1233–1240

    Article  PubMed  CAS  Google Scholar 

  • Spear AM, Loman NJ, Atkins HS, Pallen MJ (2009) Microbial TIR domains: not necessarily agents of subversion? Trends Microbiol 17:393–398

    Article  PubMed  CAS  Google Scholar 

  • Staal J, Dixelius C (2007) Tracing the ancient origins of plant innate immunity. Trends Plant Sci 12:334–342

    Article  PubMed  CAS  Google Scholar 

  • Takeda K, Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17:1–14

    Article  PubMed  CAS  Google Scholar 

  • Xu Y, Tao X, Shen B, Horng T, Medzhitov R, Manley JL, Tong L (2000) Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature 408:111–115

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto M, Takeda K, Akira S (2004) TIR domain-containing adaptors define the specificity of TLR signaling. Mol Immunol 40:861–868

    Article  PubMed  CAS  Google Scholar 

  • Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, Oliver P, Huang W, Zhang P, Zhang J, Shellito JE, Bagby GJ, Nelson S, Charrier K, Peschon JJ, Kolls JK (2001) Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med 194:519–527

    Article  PubMed  CAS  Google Scholar 

  • Ye H, Arron JR, Lamothe B, Cirilli M, Kobayashi T, Shevde NK, Segal D, Dzivenu OK, Vologodskaia M, Yim M, Du K, Singh S, Pike JW, Darnay BG, Choi Y, Wu H (2002) Distinct molecular mechanism for initiating TRAF6 signalling. Nature 418:443–447

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Dr Laurence Bugeon for providing them with a male zebrafish, Hayley Eames and Drs David Saliba and Matt Peirce (KIR, London, UK) for critical reading of the manuscript and helpful comments. The research leading to these results has received funding from the European Community’s Seventh Framework Programme FP7/2007-2013 under grant agreement number [222008].

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, 65 Aspenlea Road, Hammersmith, London, W6 8LH, UK

    Grigory Ryzhakov, Katrina Blazek & Irina A. Udalova

Authors
  1. Grigory Ryzhakov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katrina Blazek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Irina A. Udalova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Grigory Ryzhakov or Irina A. Udalova.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 194 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ryzhakov, G., Blazek, K. & Udalova, I.A. Evolution of Vertebrate Immunity: Sequence and Functional Analysis of the SEFIR Domain Family Member Act1. J Mol Evol 72, 521–530 (2011). https://doi.org/10.1007/s00239-011-9450-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00239-011-9450-7

Keywords

Search

Navigation