BioProject

Analysis of cellular response to DHODH inhibition at gene expression level. The NS1 protein of influenza virus is a major virulence factor essential for virus replication as it re-directs the host cell to promote viral protein expression. More...

Analysis of cellular response to DHODH inhibition at gene expression level. The NS1 protein of influenza virus is a major virulence factor essential for virus replication as it re-directs the host cell to promote viral protein expression. NS1 inhibits cellular mRNA processing and export, down-regulating host gene expression and enhancing viral gene expression. We report here the identification of a non-toxic quinoline carboxylic acid that reverts the inhibition of mRNA nuclear export by NS1, in the absence or presence of 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 VSV M 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. Overall design: Total RNA obtained from HBEC cells subjected to 3 hours compound 1 treatment compared to DMSO treatment. Less...