The mengovirus leader protein blocks interferon-alpha/beta 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-alpha/beta), which induce the transcription of genes that cause cells to adopt an antiviral state. Many viruses have adapted mechanisms to evade IFN-alpha/beta-mediated responses. The leader protein of mengovirus, a picornavirus, has been implicated as an IFN-alpha/beta antagonist. Here, we show that the leader inhibits the transcription of IFN-alpha/beta 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-alpha/beta 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-alpha/beta 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-alpha/beta-dependent antiviral response. These results suggest that the leader, by suppressing IRF3-mediated IFN-alpha/beta production, plays an important role in replication and dissemination of mengovirus in its host.