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Influence of PB2 host-range determinants on the intranuclear mobility of the influenza A virus polymerase

Avian influenza A viruses often do not propagate efficiently in mammalian cells. The viral polymerase protein PB2 is important for this host restriction, with amino-acid polymorphisms at residue 627 and other positions acting as ‘signatures’ of avian- or human-adapted viruses. Restriction is hypothe...

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Autores principales: Foeglein, Ágnes, Loucaides, Eva M., Mura, Manuela, Wise, Helen M., Barclay, Wendy S., Digard, Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for General Microbiology 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167894/
https://www.ncbi.nlm.nih.gov/pubmed/21471313
http://dx.doi.org/10.1099/vir.0.031492-0
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author Foeglein, Ágnes
Loucaides, Eva M.
Mura, Manuela
Wise, Helen M.
Barclay, Wendy S.
Digard, Paul
author_facet Foeglein, Ágnes
Loucaides, Eva M.
Mura, Manuela
Wise, Helen M.
Barclay, Wendy S.
Digard, Paul
author_sort Foeglein, Ágnes
collection PubMed
description Avian influenza A viruses often do not propagate efficiently in mammalian cells. The viral polymerase protein PB2 is important for this host restriction, with amino-acid polymorphisms at residue 627 and other positions acting as ‘signatures’ of avian- or human-adapted viruses. Restriction is hypothesized to result from differential interactions (either positive or inhibitory) with unidentified cellular factors. We applied fluorescence recovery after photobleaching (FRAP) to investigate the mobility of the viral polymerase in the cell nucleus using A/PR/8/34 and A/Turkey/England/50-92/91 as model strains. As expected, transcriptional activity of a polymerase with the avian PB2 protein was strongly dependent on the identity of residue 627 in human but not avian cells, and this correlated with significantly slower diffusion of the inactive polymerase in human but not avian nuclei. In contrast, the activity and mobility of the PR8 polymerase was affected much less by residue 627. Sequence comparison followed by mutagenic analyses identified residues at known host-range-specific positions 271, 588 and 701 as well as a novel determinant at position 636 as contributors to host-specific activity of both PR8 and Turkey PB2 proteins. Furthermore, the correlation between poor transcriptional activity and slow diffusional mobility was maintained. However, activity did not obligatorily correlate with predicted surface charge of the 627 domain. Overall, our data support the hypothesis of a host nuclear factor that interacts with the viral polymerase and modulates its activity. While we cannot distinguish between positive and inhibitory effects, the data have implications for how such factors might operate.
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spelling pubmed-31678942011-10-03 Influence of PB2 host-range determinants on the intranuclear mobility of the influenza A virus polymerase Foeglein, Ágnes Loucaides, Eva M. Mura, Manuela Wise, Helen M. Barclay, Wendy S. Digard, Paul J Gen Virol Animal Avian influenza A viruses often do not propagate efficiently in mammalian cells. The viral polymerase protein PB2 is important for this host restriction, with amino-acid polymorphisms at residue 627 and other positions acting as ‘signatures’ of avian- or human-adapted viruses. Restriction is hypothesized to result from differential interactions (either positive or inhibitory) with unidentified cellular factors. We applied fluorescence recovery after photobleaching (FRAP) to investigate the mobility of the viral polymerase in the cell nucleus using A/PR/8/34 and A/Turkey/England/50-92/91 as model strains. As expected, transcriptional activity of a polymerase with the avian PB2 protein was strongly dependent on the identity of residue 627 in human but not avian cells, and this correlated with significantly slower diffusion of the inactive polymerase in human but not avian nuclei. In contrast, the activity and mobility of the PR8 polymerase was affected much less by residue 627. Sequence comparison followed by mutagenic analyses identified residues at known host-range-specific positions 271, 588 and 701 as well as a novel determinant at position 636 as contributors to host-specific activity of both PR8 and Turkey PB2 proteins. Furthermore, the correlation between poor transcriptional activity and slow diffusional mobility was maintained. However, activity did not obligatorily correlate with predicted surface charge of the 627 domain. Overall, our data support the hypothesis of a host nuclear factor that interacts with the viral polymerase and modulates its activity. While we cannot distinguish between positive and inhibitory effects, the data have implications for how such factors might operate. Society for General Microbiology 2011-07 /pmc/articles/PMC3167894/ /pubmed/21471313 http://dx.doi.org/10.1099/vir.0.031492-0 Text en © 2011 SGM http://creativecommons.org/licenses/by/2.5/ 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.
spellingShingle Animal
Foeglein, Ágnes
Loucaides, Eva M.
Mura, Manuela
Wise, Helen M.
Barclay, Wendy S.
Digard, Paul
Influence of PB2 host-range determinants on the intranuclear mobility of the influenza A virus polymerase
title Influence of PB2 host-range determinants on the intranuclear mobility of the influenza A virus polymerase
title_full Influence of PB2 host-range determinants on the intranuclear mobility of the influenza A virus polymerase
title_fullStr Influence of PB2 host-range determinants on the intranuclear mobility of the influenza A virus polymerase
title_full_unstemmed Influence of PB2 host-range determinants on the intranuclear mobility of the influenza A virus polymerase
title_short Influence of PB2 host-range determinants on the intranuclear mobility of the influenza A virus polymerase
title_sort influence of pb2 host-range determinants on the intranuclear mobility of the influenza a virus polymerase
topic Animal
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167894/
https://www.ncbi.nlm.nih.gov/pubmed/21471313
http://dx.doi.org/10.1099/vir.0.031492-0
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