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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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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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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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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DOI: https://doi.org/10.1038/ni.2429
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