Abstract
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.
Highlights
Virus infections of mammals have a wide spectrum of outcomes, ranging from immediate clearance to severe disease
Given the specific nature of MAP3K8 induction by IRF7, we examined the transcriptional regulation of this kinase by standard firefly LUC assays under the control of the human MAP3K8 promoter
IRF3 is among the first transcription factors activated by pathogen-associated molecular patterns (PAMPs) recognition and induces low amounts of IFN through a stochastic process, because the enhanceosome is not optimized for IRF3 dimers [21, 65]
Summary
Virus infections of mammals have a wide spectrum of outcomes, ranging from immediate clearance to severe disease. 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. Pattern recognition receptor activation results in the assembly of a signaling complex at the mitochondrial membrane that includes MAVS ( known as IPS-I, Cardif, and VISA) and engagement of both the classical IKK and IKKrelated kinases as well as MAPKs, culminating in NFB, interferon regulatory factor (IRF), and AP1 activation, respectively [4] This coordinated activation of transcription factors leads to formation of an enhanceosome in the promoter of the primary type I interferon (IFN-I) gene product, IFN [5]. This finding provides a molecular mechanism for the amplification of the antiviral response of the cell and establishes a framework for how it is maintained at a level that is proportional to the pathogenic threat that initiated it
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