Pellino family proteins are E3 ubiquitin ligases that can regulate members of the IL-1 receptor-associated kinase (IRAK) family. This study shows that Pellino3 negatively regulates type I interferon (IFN) expression following Toll-like receptor 3 (TLR3) activation. The authors generated Pellino3-deficient mice and found that macrophages from these animals produced increased levels of IFN following TLR3 stimulation but responded in a similar manner to wild-type macrophages when treated with other TLR agonists. Notably, the enhanced IFN response of Pellino3-deficient mice promoted protective immunity to encephalomyocarditis virus (ECMV). Pellino3 negatively regulated TLR3 signalling by associating with and ubiquitylating TNF receptor associated factor 6 (TRAF6) — this blocked IFN induction by preventing TRAF6-mediated ubiquitylation and activation of interferon regulatory factor 7 (IRF7). Activation of TLR3 upregulated Pellino3 expression, suggesting that this is an autoregulatory pathway that controls type I IFN induction.
ORIGINAL RESEARCH PAPER
Siednienko, J. et al. Pellino3 targets the IRF7 pathway and facilitates autoregulation of TLR3- and viral-induced expression of type I interferons. Nature Immunol. 7 Oct 2012 (doi:10.1038/ni.2429)
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Bordon, Y. Pellino3 — a self-control strategy for TLR3. Nat Rev Immunol 12, 747 (2012). https://doi.org/10.1038/nri3337
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DOI: https://doi.org/10.1038/nri3337