When mammalian cells are invaded by viruses, the first line of defense involves production of cytokines such as interferon-β (IFN-β). A central event in this response is the activation of transcription factor NF-κB. Under normal conditions, NF-κB localizes to the cytoplasm in a complex with its inhibitor, IκBα. Upon viral infection or under the influence of certain other stimuli, IκBα is phosphorylated, ubiquitinated and degraded by the proteasome, releasing NF-κB, which then translocates to the nucleus and promotes transcription of target genes, including IFN-β. Now Herdy and colleagues find that during viral infection IκBα levels are also regulated at the level of translation. eIF4E is a low-abundance translation initiation factor whose phosphorylation status at Ser209 is altered after infection with various viruses, but the consequences of this modification were not clear. The authors compared the responses to viral infection of mouse embryonic fibroblasts expressing either wild-type or S209A eIF4E. The mutation led to impaired replication of different RNA viruses, including those whose translation does not require eIF4E, suggesting that the effect was due to altered translation of host protein(s). In fact, the S209A-expressing cells produced more IFN-β in response to stimuli than did wild-type cells, and this was responsible for inhibiting viral replication. To dissect the mechanism responsible for the higher levels of IFN-β, the authors performed genome-wide polysome analysis and found that the mRNA for IκBα was less abundant in cells expressing eIF4E S209A than in wild type; immunoblot assays revealed that IκBα protein abundance was reduced by half. Consequently, NF-κB transcriptional activity was higher in the mutant cells. Finally, the authors showed that mice expressing S209A eIF4E had better survival than wild-type animals after infection with vesicular stomatitis virus. These data indicate that dephosphorylation of eIF4E might be a host response to limit viral infection, promoting increased NF-κB activity via a translational control mechanism. (Nat. Immunol. doi:10.1038/ni.2291, published online 29 April 2012)