Optineurin negatively regulates the induction of IFNβ in response to RNA virus infection
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 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.
Citation
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 . https://doi.org/10.1371/journal.ppat.1000778
Publication
PLoS Pathogens
Status
Peer reviewed
ISSN
1553-7366Type
Journal article
Description
Work in RME laboratories is funded by the Wellcome Trust [079810/Z/06/Z].Collections
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