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Title

Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export

Authors
Zhang, Liang
Das, Priyabrata
Manicassamy, Balaji
Wang, Yaming
Deng, Xiaoyi
Cai, Ling
Tu, Benjamin P
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Published in The Journal of Cell Biology. 2012, vol. 196, no. 3, p. 315-326
Abstract 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.
Keywords Active Transport, Cell Nucleus/physiologyAnimalsCell Nucleus/metabolismCells, CulturedDogsOrthomyxoviridae/genetics/metabolismOxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors/metabolismPyrimidines/biosynthesisRNA, Messenger/metabolismRNA, Viral/metabolismViral Matrix Proteins/chemistry/metabolismViral Nonstructural Proteins/genetics/metabolismVirulenceVirulence Factors/metabolism
Identifiers
PMID: 22312003
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ZHANG, Liang et al. Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export. In: Journal of Cell Biology, 2012, vol. 196, n° 3, p. 315-326. https://archive-ouverte.unige.ch/unige:77418

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Deposited on : 2015-11-18

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