Abstract
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 IFN beta, which are pivotal for the initiation of an anti-viral state. Despite the essential role of IFN beta in the anti-viral response, there is an incomplete understanding of the negative regulation of IFN beta 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 IFN beta, 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.
Original language | English |
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Article number | e1000778 |
Pages (from-to) | - |
Number of pages | 13 |
Journal | PLoS Pathogens |
Volume | 6 |
Issue number | 2 |
DOIs | |
Publication status | Published - Feb 2010 |