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The cellular localization of avian influenza virus PB1-F2 protein alters the magnitude of IFN2 promoter and NFκB-dependent promoter antagonism in chicken cells.

James, J; Smith, N; Ross, C; Iqbal, M; Goodbourn, S; Digard, P; Barclay, WS; Shelton, H (2019) The cellular localization of avian influenza virus PB1-F2 protein alters the magnitude of IFN2 promoter and NFκB-dependent promoter antagonism in chicken cells. J Gen Virol, 100 (3). pp. 414-430. ISSN 1465-2099 https://doi.org/10.1099/jgv.0.001220
SGUL Authors: Goodbourn, Stephen Edward

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Abstract

The accessory protein, PB1-F2, of influenza A virus (IAV) functions in a chicken host to prolong infectious virus shedding and thus the transmission window. Here we show that this delay in virus clearance by PB1-F2 in chickens is accompanied by reduced transcript levels of type 1 interferon (IFN)-induced genes and NFκB-activated pro-inflammation cytokines. In vitro, two avian influenza isolate-derived PB1-F2 proteins, H9N2 UDL01 and H5N1 5092, exhibited the same antagonism of the IFN and pro-inflammation induction pathways seen in vivo, but to different extents. The two PB1-F2 proteins had different cellular localization in chicken cells, with H5N1 5092 being predominantly mitochondrial-associated and H9N2 UDL being cytoplasmic but not mitochondrial-localized. We hypothesized that PB1-F2 localization might influence the functionality of the protein during infection and that the protein sequence could alter cellular localization. We demonstrated that the sequence of the C-terminus of PB1-F2 determined cytoplasmic localization in chicken cells and this was linked with protein instability. Mitochondrial localization of PB1-F2 resulted in reduced antagonism of an NFκB-dependent promoter. In parallel, mitochondrial localization of PB1-F2 increased the potency of chicken IFN 2 induction antagonism. We suggest that mitochondrial localization of PB1-F2 restricts interaction with cytoplasmic-located IKKβ, reducing NFκB-responsive promoter antagonism, but enhances antagonism of the IFN2 promoter through interaction with the mitochondrial adaptor MAVS. Our study highlights the differential mechanisms by which IAV PB1-F2 protein can dampen the avian host innate signalling response.

Item Type: Article
Additional Information: © 2019 The Authors This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: 06 Biological Sciences, 07 Agricultural And Veterinary Sciences, 11 Medical And Health Sciences, Virology
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: J Gen Virol
ISSN: 1465-2099
Language: eng
Dates:
DateEvent
1 March 2019Published
23 January 2019Published Online
25 December 2018Accepted
Publisher License: Creative Commons: Attribution 3.0
Projects:
Project IDFunderFunder ID
BB/K002465/1Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BBS/E/00001759Pirbright Institutehttp://dx.doi.org/10.13039/501100000870
BBS/E/I/00001650Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BBS/E/I/00007034Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BBS/E/I/00007038Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
PubMed ID: 30672726
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/110533
Publisher's version: https://doi.org/10.1099/jgv.0.001220

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