Induction of IRF‐3/‐7 kinase and NF‐κB in response to double‐stranded RNA and virus infection: common and unique pathways

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Abstract
Backgrounds: Infection by virus or treatment with double‐stranded RNA (dsRNA) results in the activation of transcription factors including IRF‐3, IRF‐7 and a pleiotropic regulator NF‐κB by specific phosphorylation. These factors are important in triggering a cascade of antiviral responses. A protein kinase that is yet to be identified is responsible for the activation of these factors and plays a key role in the responses.Results: The signal cascade was analysed using sensitive assays for the activation of IRF‐3 and NF‐κB, and various inhibitors. We found that the activation of IRF‐3 and NF‐κB by dsRNA or virus involves a process that is sensitive to Geldanamycin. Although the induction of NF‐κB by dsRNA/virus and TNF‐α involves common downstream pathways including IKK activation, the upstream, Geldanamycin‐sensitive process was unique to the dsRNA/virus‐induced signal. By an in vitro assay using cell extract, we found an inducible protein kinase activity with physiological specificity of IRF‐3 phosphorylation. Furthermore, the same extract specifically phosphorylated IRF‐7 in a similar manner.Conclusions: Double‐stranded RNA or virus triggers a specific signal cascade that results in the activation of the IRF‐3/‐7 kinase we detected, which corresponds to the long‐sought signalling machinery that is responsible for triggering the early phase of innate response. The signal branches to a common NF‐κB activation cascade, thus resulting in the activation of a set of critical transcription factors for the response.