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 IKKε (IκB kinase ε), enhances it activation, and then facilitates phosphorylation of the transcription factor IRF3 by IKKε. However, the TLR7/9 (Toll-like receptor 7/9)-mediated pathway, one of the most physiologically relevant IFN induction pathways, proceeds independently of IKKε or the related kinase TBK1 (TANK-binding kinase 1). This pathway induces type I IFN production via the kinases NIK (NF-κB-inducing kinase) and IKKα and is activated when plasmacytoid dendritic cells sense viral nucleic acids. In the present study, we demonstrate that DDX3 also directly interacts with IKKα and enhances its autophosphorylation and -activation. Modulation of DDX3 expression consequently affected NIK/IKKα-mediated IRF7 phosphorylation and induction of type I interferons. In addition, alternative NF-κB (nuclear factor-κB) activation, another pathway regulated by NIK and IKKα, was also down-regulated in DDX3 knockdown cells. This substantially broadens the effects of DDX3 in innate immune signalling to pathways beyond TBK1/IKKε 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.
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In this issue Moreira and colleagues provide insights into leptin signaling and male reproductive health and ask if leptin signaling is the missing link between obesity and subfertility. The cover image shows a representation of leptin signaling pathways. Circulating leptin bounds to the long isoform of leptin receptor (LepRb), which activates JAK2 tyrosine kinase, triggering a cascade of downstream signaling pathways. For further details, see pages 3535–3560.
DDX3 directly facilitates IKKα activation and regulates downstream signalling pathways
Anthony Fullam, Lili Gu, Yvette Höhn, Martina Schröder; DDX3 directly facilitates IKKα activation and regulates downstream signalling pathways. Biochem J 30 November 2018; 475 (22): 3595–3607. doi: https://doi.org/10.1042/BCJ20180163
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