The mengovirus leader protein blocks interferon‐α/β gene transcription and inhibits activation of interferon regulatory factor 3

Viral infection of mammalian cells triggers the synthesis and secretion of type I interferons (i.e. IFN‐α/β), which induce the transcription of genes that cause cells to adopt an antiviral state. Many viruses have adapted mechanisms to evade IFN‐α/β‐mediated responses. The leader protein of mengovirus, a picornavirus, has been implicated as an IFN‐α/β antagonist. Here, we show that the leader inhibits the transcription of IFN‐α/β and that both the presence of a zinc finger motif in its N‐terminus and phosphorylation of threonine‐47 are required for this function. Transcription of IFN‐α/β genes relies on the activity of a number of transcription factors, including interferon regulatory factor 3 (IRF‐3). We show that the leader interferes with the transactivation activity of IRF‐3 by interfering with its dimerization. Accordingly, mutant viruses with a disturbed leader function were impaired in their ability to suppress IFN‐α/β transcription in vivo. By consequence, the leader mutant viruses had an impaired ability to replicate and spread in normal mice but not in IFNAR‐KO mice, which are incapable of mounting an IFN‐α/β‐dependent antiviral response. These results suggest that the leader, by suppressing IRF3‐mediated IFN‐α/β production, plays an important role in replication and dissemination of mengovirus in its host.