Journal
PLOS PATHOGENS
Volume 6, Issue 2, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1000778
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Funding
- RCUK
- MRC [G0401577]
- Yorkshire Cancer Research [L339]
- Welcome Trust [079699/Z/06/Z, 079810/Z/06/Z]
- Biotechnology and Biological Sciences Research Council [BB/D524875/1] Funding Source: researchfish
- Medical Research Council [G0401577] Funding Source: researchfish
- BBSRC [BB/D524875/1] Funding Source: UKRI
- MRC [G0401577] Funding Source: UKRI
- Wellcome Trust [079699/Z/06/Z, 079810/Z/06/Z] Funding Source: Wellcome Trust
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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 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.
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