Optineurin negatively regulates the induction of IFNβ in response to RNA virus infection
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The innate immune response provides a critical defense against microbial infections, including viruses. These are recognised by pattern recognition receptors including Toll-like receptors (TLRs) and RIG-I like helicases (RLHs). Detection of virus triggers signalling cascades that induce transcription of type I interferons including IFNb, which are pivotal for the initiation of an anti-viral state. Despite the essential role of IFNb in the anti-viral response, there is an incomplete understanding of the negative regulation of IFNb induction. Here we provide evidence that expression of the Nemo-related protein, optineurin (NRP/FIP2), has a role in the inhibition of virus-triggered IFNb induction. Over-expression of optineurin inhibited Sendaivirus (SeV) and dsRNA triggered induction of IFNb, whereas depletion of optineurin with siRNA promoted virus-induced IFNb production and decreased RNA virus replication. Immunoprecipitation and immunofluorescence studies identified optineurin in a protein complex containing the antiviral protein kinase TBK1 and the ubiquitin ligase TRAF3. Furthermore, mutagenesis studies determined that binding of ubiquitin was essential for both the correct sub-cellular localisation and the inhibitory function of optineurin. This work identifies optineurin as a critical regulator of antiviral signalling and potential target for future antiviral therapy.
Mankouri , J , Fragkoudis , R , Richards , K , Wetherill , L , Harris , M , Kohl , A , Elliott , R M & MacDonald , A 2010 , ' Optineurin negatively regulates the induction of IFNβ in response to RNA virus infection ' PLoS Pathogens , vol. 6 , no. 2 , e1000778 . DOI: 10.1371/journal.ppat.1000778
(c) 2010 Mankouri et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DescriptionWork in RME laboratories is funded by the Wellcome Trust [079810/Z/06/Z].
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