Optineurin negatively regulates the induction of IFNbeta in response to RNA virus infection.

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 IFNbeta, which are pivotal for the initiation ...
of an anti-viral state. Despite the essential role of IFNbeta in the anti-viral response, there is an incomplete understanding of the negative regulation of IFNbeta induction. Here we provide evidence that expression of the Nemo-related protein, optineurin (NRP/FIP2), has a role in the inhibition of virus-triggered IFNbeta induction. Over-expression of optineurin inhibited Sendai-virus (SeV) and dsRNA triggered induction of IFNbeta, whereas depletion of optineurin with siRNA promoted virus-induced IFNbeta 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.
Mesh Terms:
Blotting, Western, Fluorescent Antibody Technique, Gene Expression, Gene Expression Regulation, Viral, Humans, Immunoprecipitation, Interferon-beta, Respirovirus Infections, Reverse Transcriptase Polymerase Chain Reaction, Sendai virus, Signal Transduction, Transcription Factor TFIIIA, Transfection
PLoS Pathog.
Date: Feb. 01, 2010
Download Curated Data For This Publication
140143
Switch View:
  • Interactions 7