Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKɛ-mediated IRF activation

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Abstract
Viruses are detected by different classes of pattern recognition receptors (PRRs), such as Toll‐like receptors and RIG‐like helicases. Engagement of PRRs leads to activation of interferon (IFN)‐regulatory factor 3 (IRF3) and IRF7 through IKKε and TBK1 and consequently IFN‐β induction. Vaccinia virus (VACV) encodes proteins that manipulate host signalling, sometimes by targeting uncharacterised proteins. Here, we describe a novel VACV protein, K7, which can inhibit PRR‐induced IFN‐β induction by preventing TBK1/IKKε‐mediated IRF activation. We identified DEAD box protein 3 (DDX3) as a host target of K7. Expression of DDX3 enhanced Ifnb promoter induction by TBK1/IKKε, whereas knockdown of DDX3 inhibited this, and virus‐ or dsRNA‐induced IRF3 activation. Further, dominant‐negative DDX3 inhibited virus‐, dsRNA‐ and cytosolic DNA‐stimulated Ccl5 promoter induction, which is also TBK1/IKKε dependent. Both K7 binding and enhancement of Ifnb induction mapped to the N‐terminus of DDX3. Furthermore, virus infection induced an association between DDX3 and IKKε. Therefore, this study shows for the first time the involvement of a DEAD box helicase in TBK1/IKKε‐mediated IRF activation and Ifnb promoter induction.