Inhibitors of pyrimidine synthesis can stop the influenza virus from trapping host cell mRNAs in the nucleus, Zhang et al. report.
Many viruses switch off the expression of host cell genes in order to survive and replicate. The influenza virus, for example, produces a factor called NS1 that blocks the export of host mRNAs from the nucleus, in part by binding to the mRNA export factor NXF1. By screening a library of small molecules, Zhang et al. found that mRNA export was restored in NS1-expressing cells by inhibitors of dihydroorotate dehydrogenase (DHODH), a cellular enzyme required for the de novo synthesis of pyrimidines like cytosine, thymine, and uracil.
Restoring mRNA export allowed cells to express antiviral factors including the transcription factor HIF1-α. DHODH inhibitors rescued mRNA export in influenza virus–infected cells and blocked viral replication, effects that were mitigated if the cells were supplemented with extra pyrimidines. DHODH inhibitors also reversed the ability of the vesicular stomatitis virus M protein to block mRNA export, the researchers found.
NXF1 levels rose when pyrimidine synthesis was blocked, and DHODH inhibitors couldn't restore mRNA export to cells lacking this mRNA export factor. Zhang et al. don't yet know how pyrimidine levels influence NXF1 expression. Senior author Beatriz Fontoura speculates that pyrimidine synthesis may also be linked to mRNA export because many nuclear transport proteins are modified with N-acetylglucosamine, a process that requires the pyrimidine-based nucleotides UDP and UTP.