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Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export
The NS1 protein of influenza virus is a major virulence factor essential for virus replication, as it redirects the host cell to promote viral protein expression. NS1 inhibits cellular messenger ribonucleic acid (mRNA) processing and export, down-regulating host gene expression and enhancing viral g...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3275370/ https://www.ncbi.nlm.nih.gov/pubmed/22312003 http://dx.doi.org/10.1083/jcb.201107058 |
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author | Zhang, Liang Das, Priyabrata Schmolke, Mirco Manicassamy, Balaji Wang, Yaming Deng, Xiaoyi Cai, Ling Tu, Benjamin P. Forst, Christian V. Roth, Michael G. Levy, David E. García-Sastre, Adolfo de Brabander, Jef Phillips, Margaret A. Fontoura, Beatriz M.A. |
author_facet | Zhang, Liang Das, Priyabrata Schmolke, Mirco Manicassamy, Balaji Wang, Yaming Deng, Xiaoyi Cai, Ling Tu, Benjamin P. Forst, Christian V. Roth, Michael G. Levy, David E. García-Sastre, Adolfo de Brabander, Jef Phillips, Margaret A. Fontoura, Beatriz M.A. |
author_sort | Zhang, Liang |
collection | PubMed |
description | The NS1 protein of influenza virus is a major virulence factor essential for virus replication, as it redirects the host cell to promote viral protein expression. NS1 inhibits cellular messenger ribonucleic acid (mRNA) processing and export, down-regulating host gene expression and enhancing viral gene expression. We report in this paper the identification of a nontoxic quinoline carboxylic acid that reverts the inhibition of mRNA nuclear export by NS1, in the absence or presence of the virus. This quinoline carboxylic acid directly inhibited dihydroorotate dehydrogenase (DHODH), a host enzyme required for de novo pyrimidine biosynthesis, and partially reduced pyrimidine levels. This effect induced NXF1 expression, which promoted mRNA nuclear export in the presence of NS1. The release of NS1-mediated mRNA export block by DHODH inhibition also occurred in the presence of vesicular stomatitis virus M (matrix) protein, another viral inhibitor of mRNA export. This reversal of mRNA export block allowed expression of antiviral factors. Thus, pyrimidines play a necessary role in the inhibition of mRNA nuclear export by virulence factors. |
format | Online Article Text |
id | pubmed-3275370 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-32753702012-08-06 Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export Zhang, Liang Das, Priyabrata Schmolke, Mirco Manicassamy, Balaji Wang, Yaming Deng, Xiaoyi Cai, Ling Tu, Benjamin P. Forst, Christian V. Roth, Michael G. Levy, David E. García-Sastre, Adolfo de Brabander, Jef Phillips, Margaret A. Fontoura, Beatriz M.A. J Cell Biol Research Articles The NS1 protein of influenza virus is a major virulence factor essential for virus replication, as it redirects the host cell to promote viral protein expression. NS1 inhibits cellular messenger ribonucleic acid (mRNA) processing and export, down-regulating host gene expression and enhancing viral gene expression. We report in this paper the identification of a nontoxic quinoline carboxylic acid that reverts the inhibition of mRNA nuclear export by NS1, in the absence or presence of the virus. This quinoline carboxylic acid directly inhibited dihydroorotate dehydrogenase (DHODH), a host enzyme required for de novo pyrimidine biosynthesis, and partially reduced pyrimidine levels. This effect induced NXF1 expression, which promoted mRNA nuclear export in the presence of NS1. The release of NS1-mediated mRNA export block by DHODH inhibition also occurred in the presence of vesicular stomatitis virus M (matrix) protein, another viral inhibitor of mRNA export. This reversal of mRNA export block allowed expression of antiviral factors. Thus, pyrimidines play a necessary role in the inhibition of mRNA nuclear export by virulence factors. The Rockefeller University Press 2012-02-06 /pmc/articles/PMC3275370/ /pubmed/22312003 http://dx.doi.org/10.1083/jcb.201107058 Text en © 2012 Zhang et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Research Articles Zhang, Liang Das, Priyabrata Schmolke, Mirco Manicassamy, Balaji Wang, Yaming Deng, Xiaoyi Cai, Ling Tu, Benjamin P. Forst, Christian V. Roth, Michael G. Levy, David E. García-Sastre, Adolfo de Brabander, Jef Phillips, Margaret A. Fontoura, Beatriz M.A. Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export |
title | Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export |
title_full | Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export |
title_fullStr | Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export |
title_full_unstemmed | Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export |
title_short | Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export |
title_sort | inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mrna nuclear export |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3275370/ https://www.ncbi.nlm.nih.gov/pubmed/22312003 http://dx.doi.org/10.1083/jcb.201107058 |
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