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

PLoS Pathog. 2010 Feb 19;6(2):e1000778. doi: 10.1371/journal.ppat.1000778.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Fluorescent Antibody Technique
  • Gene Expression
  • Gene Expression Regulation, Viral*
  • Humans
  • Immunoprecipitation
  • Interferon-beta / biosynthesis*
  • Interferon-beta / genetics
  • Respirovirus Infections / genetics
  • Respirovirus Infections / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sendai virus
  • Signal Transduction / physiology*
  • Transcription Factor TFIIIA / metabolism*
  • Transfection

Substances

  • OPTN protein, human
  • Transcription Factor TFIIIA
  • Interferon-beta