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    DDX3 directly facilitates IKKα activation and regulates downstream signalling pathways

    Fullam, Anthony and Gu, Lili and Höhn, Yvette and Schroeder, Martina (2018) DDX3 directly facilitates IKKα activation and regulates downstream signalling pathways. Biochemical Journal, 475. pp. 3595-3607. ISSN 0264-6021

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    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.

    Item Type: Article
    Keywords: alternative NF-κB activation; DDX3X; DEAD-box helicase; IκB kinase; interferon induction; Toll-like receptor signalling;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 13199
    Identification Number:
    Depositing User: Martina Schroeder
    Date Deposited: 28 Aug 2020 13:50
    Journal or Publication Title: Biochemical Journal
    Publisher: Portland Press
    Refereed: Yes
    Use Licence: This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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