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Vaccinia virus protein C4 inhibits NF-κB activation and promotes virus virulence

Vaccinia virus (VACV) strain Western Reserve protein C4 has been characterized and its function and contribution to virus virulence assessed. Bioinformatic analysis showed that C4 is conserved in six orthopoxvirus species and shares 43 % amino acid identity with VACV protein C16, a known virulence f...

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Autores principales: Ember, Stuart W. J., Ren, Hongwei, Ferguson, Brian J., Smith, Geoffrey L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for General Microbiology 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3541790/
https://www.ncbi.nlm.nih.gov/pubmed/22791606
http://dx.doi.org/10.1099/vir.0.045070-0
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author Ember, Stuart W. J.
Ren, Hongwei
Ferguson, Brian J.
Smith, Geoffrey L.
author_facet Ember, Stuart W. J.
Ren, Hongwei
Ferguson, Brian J.
Smith, Geoffrey L.
author_sort Ember, Stuart W. J.
collection PubMed
description Vaccinia virus (VACV) strain Western Reserve protein C4 has been characterized and its function and contribution to virus virulence assessed. Bioinformatic analysis showed that C4 is conserved in six orthopoxvirus species and shares 43 % amino acid identity with VACV protein C16, a known virulence factor. A recombinant VACV expressing a C-terminally tagged version of C4 showed that, like C16, this 37 kDa protein is expressed early during infection and localizes to both the cytoplasm and the nucleus. Functional assays using a firefly luciferase reporter plasmid under the control of a nuclear factor kappa B (NF-κB)-dependent promoter demonstrated that C4 inhibits NF-κB activation at, or downstream of, the inhibitor of kappa kinase (IKK) complex. Consistent with this, C4 inhibited interleukin-1β-induced translocation of p65 into the nucleus. A VACV lacking the C4L gene (vΔC4) showed no significant differences from wild-type virus in growth kinetics or spread in cell culture, but had reduced virulence in a murine intranasal model of infection. vΔC4-infected mice exhibited fewer symptoms, lost less weight and recovered 7 days earlier than animals infected with control viruses expressing C4. Furthermore, bronchoalveolar lavage fluid from vΔC4-infected mice had increased cell numbers at day 5 post-infection, which correlated with reduced lung virus titres from this time onward. C4 represents the ninth VACV protein to inhibit NF-κB activation and remarkably, in every case examined, loss of each protein individually caused an alteration in virus virulence, despite the presence of other NF-κB inhibitors.
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spelling pubmed-35417902013-04-24 Vaccinia virus protein C4 inhibits NF-κB activation and promotes virus virulence Ember, Stuart W. J. Ren, Hongwei Ferguson, Brian J. Smith, Geoffrey L. J Gen Virol Animal Vaccinia virus (VACV) strain Western Reserve protein C4 has been characterized and its function and contribution to virus virulence assessed. Bioinformatic analysis showed that C4 is conserved in six orthopoxvirus species and shares 43 % amino acid identity with VACV protein C16, a known virulence factor. A recombinant VACV expressing a C-terminally tagged version of C4 showed that, like C16, this 37 kDa protein is expressed early during infection and localizes to both the cytoplasm and the nucleus. Functional assays using a firefly luciferase reporter plasmid under the control of a nuclear factor kappa B (NF-κB)-dependent promoter demonstrated that C4 inhibits NF-κB activation at, or downstream of, the inhibitor of kappa kinase (IKK) complex. Consistent with this, C4 inhibited interleukin-1β-induced translocation of p65 into the nucleus. A VACV lacking the C4L gene (vΔC4) showed no significant differences from wild-type virus in growth kinetics or spread in cell culture, but had reduced virulence in a murine intranasal model of infection. vΔC4-infected mice exhibited fewer symptoms, lost less weight and recovered 7 days earlier than animals infected with control viruses expressing C4. Furthermore, bronchoalveolar lavage fluid from vΔC4-infected mice had increased cell numbers at day 5 post-infection, which correlated with reduced lung virus titres from this time onward. C4 represents the ninth VACV protein to inhibit NF-κB activation and remarkably, in every case examined, loss of each protein individually caused an alteration in virus virulence, despite the presence of other NF-κB inhibitors. Society for General Microbiology 2012-10 /pmc/articles/PMC3541790/ /pubmed/22791606 http://dx.doi.org/10.1099/vir.0.045070-0 Text en © 2012 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
Ember, Stuart W. J.
Ren, Hongwei
Ferguson, Brian J.
Smith, Geoffrey L.
Vaccinia virus protein C4 inhibits NF-κB activation and promotes virus virulence
title Vaccinia virus protein C4 inhibits NF-κB activation and promotes virus virulence
title_full Vaccinia virus protein C4 inhibits NF-κB activation and promotes virus virulence
title_fullStr Vaccinia virus protein C4 inhibits NF-κB activation and promotes virus virulence
title_full_unstemmed Vaccinia virus protein C4 inhibits NF-κB activation and promotes virus virulence
title_short Vaccinia virus protein C4 inhibits NF-κB activation and promotes virus virulence
title_sort vaccinia virus protein c4 inhibits nf-κb activation and promotes virus virulence
topic Animal
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3541790/
https://www.ncbi.nlm.nih.gov/pubmed/22791606
http://dx.doi.org/10.1099/vir.0.045070-0
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