Mitogen-activated Protein Kinase-mediated Licensing of Interferon Regulatory Factor 3/7 Reinforces the Cell Response to Virus

The induction of the intrinsic antiviral defense in mammals relies on the accumulation of foreign genetic material. As such, complete engagement of this response is limited to replication-competent viruses. Interferon regulatory factors (IRFs) are mediators of this defense with shared enhancer elements but display a spectrum of transcriptional potential. Here we describe a mechanism designed to enhance this response should a pathogen not be successfully inhibited. We find that activation of IRF7 results in the induction of MAP3K8 and restructuring of the antiviral transcriptome. MAP3K8 mediates the phosphorylation and repression of IRF3 homodimers to promote greater transcriptional activity through utilization of IRF3:IRF7 heterodimers. Among the genes influenced by the MAP3K8/IRF7 signaling axis are members of the SP100 gene family that serve as general transcriptional enhancers of the antiviral defense. We propose that this feed forward loop serves to reinforce the cellular response and is reserved for imminent threats to the host.