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

Journal of Molecular Evolution volume 72, pages 521–530 (2011)Cite this article

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.

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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.

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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

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  1. Grigory Ryzhakov
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  2. Katrina Blazek
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  3. Irina A. Udalova
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Correspondence to Grigory Ryzhakov or Irina A. Udalova.

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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

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

Keywords

  • Act1/CIKS
  • SEFIR
  • NF-κB
  • TRAF6
  • IL-17