title: Optineurin negatively regulates the induction of IFNbeta 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 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.
authors.affiliation: Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
authors.forename: Jamel
authors.initials: J
authors.lastname: Mankouri
authors.forename: Rennos
authors.initials: R
authors.lastname: Fragkoudis
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: Richards
authors.forename: Laura F
authors.initials: LF
authors.lastname: Wetherill
authors.forename: Mark
authors.initials: M
authors.lastname: Harris
authors.forename: Alain
authors.initials: A
authors.lastname: Kohl
authors.forename: Richard M
authors.initials: RM
authors.lastname: Elliott
authors.forename: Andrew
authors.initials: A
authors.lastname: Macdonald
mesh_terms: D015153:Blotting, Western; D018797:Cell Cycle Proteins; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D015967:Gene Expression Regulation, Viral; D006801:Humans; D047468:Immunoprecipitation; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D026901:Membrane Transport Proteins; D010253:Respirovirus Infections / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029082:Sendai virus; D015398:Signal Transduction / Q000502:physiology*; D035582:Transcription Factor TFIIIA / Q000378:metabolism*; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; D026901:Membrane Transport Proteins; C409460:OPTN protein, human; D035582:Transcription Factor TFIIIA; D016899:Interferon-beta