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Pellino3 targets the IRF7 pathway and facilitates autoregulation of TLR3- and viral-induced expression of type I interferons

Nature Immunology volume 13, pages 1055–1062 (2012)Cite this article

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Abstract

Toll-like receptors (TLRs) sense pathogen-associated molecules and respond by inducing cytokines and type I interferon. Here we show that genetic ablation of the E3 ubiquitin ligase Pellino3 augmented the expression of type I interferon but not of proinflammatory cytokines in response to TLR3 activation. Pellino3-deficient mice had greater resistance against the pathogenic and lethal effects of encephalomyocarditis virus (EMCV). TLR3 signaling induced Pellino3, which in turn interacted with and ubiquitinated TRAF6. This modification suppressed the ability of TRAF6 to interact with and activate IRF7, resulting in downregulation of type I interferon expression. Our findings highlight a new physiological role for Pellino3 and define a new autoregulatory network for controlling type I interferon expression.

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Figure 1: Pellino3 deficiency results in enhanced TLR3-induced expression of IFN-β and related genes.
Figure 2: Pellino3-deficient cells exhibit an enhanced type 1 interferon response to EMCV infection.
Figure 3: Peli3−/− mice exhibit augmented IFN-β expression and increased viral clearance in response to EMCV infection.
Figure 4: Pellino3 inhibits activation and nuclear translocation of IRF7.
Figure 5: Loss of Pellino3 enhances binding of TRAF6 to IRF7 and ubiquitination of IRF7.
Figure 6: Pellino3 mediates TLR3-induced ubiquitination of TRAF6, which negatively regulates ubiquitination of IRF7 and expression of IFN-β.

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Acknowledgements

This work was funded by Science Foundation Ireland (07/IN.1/B972) and the Health Research Board of Ireland (under grant PhD/2007/09). We thank B. Cloak and S.Worrell for technical assistance with photomicroscopy, and M. Healy for assistance with flow cytometry.

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  1. Jakub Siednienko, Ruaidhri Jackson and Mark Mellett: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biology, Institute of Immunology, National University of Ireland Maynooth, Maynooth, County Kildare, Ireland.,

    Jakub Siednienko, Ruaidhri Jackson, Mark Mellett, Nezira Delagic, Shuo Yang, Bingwei Wang, Lisa S Tang, Bernard P Mahon & Paul N Moynagh

  2. University College Dublin (UCD) School of Veterinary Medicine, Dublin, Ireland

    John J Callanan

  3. Conway Institute of Biomolecular and Biomedical Research, UCD, Belfield, Dublin, Ireland.,

    John J Callanan

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Contributions

J.S., R.J. and M.M. developed the concept, designed and performed experiments, analyzed data and prepared the figures; N.D., S.Y., B.W. and L.S.T. designed and performed experiments and analyzed data; J.J.C. performed general pathology screening and the pathology-related experiments on heart samples; B.P.M. designed and supervised the EMCV infection studies; P.N.M. conceived the study, supervised the project, analyzed data and wrote the manuscript.

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Correspondence to Paul N Moynagh.

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Siednienko, J., Jackson, R., Mellett, M. et al. Pellino3 targets the IRF7 pathway and facilitates autoregulation of TLR3- and viral-induced expression of type I interferons. Nat Immunol 13, 1055–1062 (2012). https://doi.org/10.1038/ni.2429

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