TY - JOUR
T1 - Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export
AU - Zhang, Liang
AU - Das, Priyabrata
AU - Schmolke, Mirco
AU - Manicassamy, Balaji
AU - Wang, Yaming
AU - Deng, Xiaoyi
AU - Cai, Ling
AU - Tu, Benjamin P.
AU - Forst, Christian V.
AU - Roth, Michael G.
AU - Levy, David E.
AU - García-Sastre, Adolfo
AU - de Brabander, Jef
AU - Phillips, Margaret A.
AU - Fontoura, Beatriz M A
PY - 2012/2/6
Y1 - 2012/2/6
N2 - 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.
AB - 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.
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U2 - 10.1083/jcb.201107058
DO - 10.1083/jcb.201107058
M3 - Article
C2 - 22312003
AN - SCOPUS:84859407901
SN - 0021-9525
VL - 196
SP - 315
EP - 326
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 3
ER -