Optineurin Negatively Regulates the Induction of IFN beta in Response to RNA Virus Infection

Jamel Mankouri, Rennos Fragkoudis, Kathryn H. Richards, Laura F. Wetherill, Mark Harris, Alain Kohl, Richard M. Elliott, Andrew Macdonald

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Article numbere1000778
Pages (from-to)-
Number of pages13
JournalPLoS Pathogens
Volume6
Issue number2
DOIs
Publication statusPublished - Feb 2010

Fingerprint

Dive into the research topics of 'Optineurin Negatively Regulates the Induction of IFN beta in Response to RNA Virus Infection'. Together they form a unique fingerprint.

Cite this