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

Mankouri, J., Fragkoudis, R., Richards, K.H., Wetherill, L.F., Harris, M., Kohl, A. , Elliott, R.M. and Macdonald, A. (2010) Optineurin negatively regulates the induction of IFNβ in response to RNA virus infection. PLoS Pathogens, 6(2), e1000778. (doi:10.1371/journal.ppat.1000778)

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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 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 TRAF<sub>3</sub>. 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Elliott, Professor Richard and Kohl, Professor Alain
Authors: Mankouri, J., Fragkoudis, R., Richards, K.H., Wetherill, L.F., Harris, M., Kohl, A., Elliott, R.M., and Macdonald, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Published Online:19 February 2010
Copyright Holders:Copyright © 2010 The Authors
First Published:First published in PLoS ONE 6(2):e100077
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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