DDX3 directly facilitates IKK alpha activation and regulates downstream signalling pathways

DDX3 is a DEAD-box RNA helicase that we and others have previously implicated in antiviral immune signalling pathways leading to type I interferon (IFN) induction. We previously demonstrated that it directly interacts with the kinase IKK epsilon (I kappa B kinase epsilon), enhances it activation, and then facilitates phosphorylation of the transcription factor IRF3 by IKK epsilon. However, the TLR7/9 (Toll-like receptor 7/9)-mediated pathway, one of the most physiologically relevant IFN induction pathways, proceeds independently of IKK epsilon or the related kinase TBK1 (TANK-binding kinase 1). This pathway induces type I IFN production via the kinases NIK (NF-kappa B-inducing kinase) and IKK alpha and is activated when plasmacytoid dendritic cells sense viral nucleic acids. In the present study, we demonstrate that DDX3 also directly interacts with IKK alpha and enhances its autophosphorylation and -activation. Modulation of DDX3 expression consequently affected NIK/IKK alpha-mediated IRF7 phosphorylation and induction of type I interferons. In addition, alternative NF-kappa B (nuclear factor-kappa B) activation, another pathway regulated by NIK and IKK alpha, was also down-regulated in DDX3 knockdown cells. This substantially broadens the effects of DDX3 in innate immune signalling to pathways beyond TBK1/IKK epsilon and IFN induction. Dysregulation of these pathways is involved in disease states, and thus, our research might implicate DDX3 as a potential target for their therapeutic manipulation.