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

PLoS Pathogens

Richard M. Elliott¹  Mark Harris²  Laura F. Wetherill²  Andrew Macdonald²  Jamel Mankouri²  Kathryn H. Richards²  Rennos Fragkoudis³  Alain Kohl³ 

[1] Centre for Biomolecular Sciences, University of St. Andrews, Fife, United Kingdom;Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom;The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine & Veterinary Medicine, Summerhall, Edinburgh, United Kingdom

关键词: Small interfering RNAs;    Immunoprecipitation;    Luciferase;    Immune receptor signaling;    Immunoblotting;    Interferons;    Protein kinase signaling cascade;    Vesicles;   

DOI  :  10.1371/journal.ppat.1000778

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 IFNβ, which are pivotal for the initiation of an anti-viral state. Despite the essential role of IFNβ in the anti-viral response, there is an incomplete understanding of the negative regulation of IFNβ induction. Here we provide evidence that expression of the Nemo-related protein, optineurin (NRP/FIP2), has a role in the inhibition of virus-triggered IFNβ induction. Over-expression of optineurin inhibited Sendai-virus (SeV) and dsRNA triggered induction of IFNβ, whereas depletion of optineurin with siRNA promoted virus-induced IFNβ 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.

【 授权许可】

CC BY