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 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.
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Liang
L
Zhang
Priyabrata
P
Das
Mirco
M
Schmolke
Balaji
B
Manicassamy
Yaming
Y
Wang
Xiaoyi
X
Deng
Ling
L
Cai
Benjamin P
BP
Tu
Christian V
CV
Forst
Michael G
MG
Roth
David E
DE
Levy
Adolfo
A
García-Sastre
Jef
J
de Brabander
Margaret A
MA
Phillips
Beatriz M A
BM
Fontoura
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D000090722:Dihydroorotate Dehydrogenase; D004285:Dogs; D009975:Orthomyxoviridae / Q000235:genetics / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism*; D012367:RNA, Viral / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism*
D000090722:Dihydroorotate Dehydrogenase; C085820:INS1 protein, influenza virus; C094460:M protein, Vesicular stomatitis virus; D011743:Pyrimidines; D012333:RNA, Messenger; D012367:RNA, Viral; D014763:Viral Matrix Proteins; D017361:Viral Nonstructural Proteins; D037521:Virulence Factors; D044925:Oxidoreductases Acting on CH-CH Group Donors; C030986:pyrimidine