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    Human DEAD Box Helicase 3 Couples IκB Kinase ε to Interferon Regulatory Factor 3 Activation


    Gu, Lili and Fullam, Anthony and Brennan, Ruth and Schroeder, Martina (2013) Human DEAD Box Helicase 3 Couples IκB Kinase ε to Interferon Regulatory Factor 3 Activation. Molecular and Cellular Biology, 33 (10). pp. 2004-2015. ISSN 0270-7306

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    Abstract

    The human DEAD box protein 3 (DDX3) has been implicated in different processes contributing to gene expression. Interestingly, DDX3 is required as an essential host factor for the replication of HIV and hepatitis C virus (HCV) and is therefore considered a potential drug target. On the other hand, DDX3 interacts with IκB kinase ε (IKKε) and TANK-binding kinase 1 (TBK1) and contributes to the induction of antiviral type I interferons (IFNs). However, the molecular mechanism by which DDX3 contributes to IFN induction remains unclear. Here we show that DDX3 mediates phosphorylation of interferon regulatory factor 3 (IRF3) by the kinase IKKε. DDX3 directly interacts with IKKε and enhances its autophosphorylation and activation. IKKε then phosphorylates several serine residues in the N terminus of DDX3. Phosphorylation of DDX3 at serine 102 (S102) is required for recruitment of IRF3 to DDX3, facilitating its phosphorylation by IKKε. Mutation of S102 to alanine disrupted the interaction between DDX3 and IRF3 but not that between DDX3 and IKKε. The S102A mutation failed to enhance ifnb promoter activation, suggesting that the DDX3-IRF3 interaction is crucial for this effect. Our data implicates DDX3 as a scaffolding adaptor that directly facilitates phosphorylation of IRF3 by IKKε. DDX3 might thus be involved in pathway-specific activation of IRF3.

    Item Type: Article
    Additional Information: This article is available at Gu, L., Fullam, A., Brennan, R., & Schröder, M. (2013). Human DEAD Box Helicase 3 Couples IκB Kinase ε to Interferon Regulatory Factor 3 Activation. Molecular and Cellular Biology, 33(10), 2004–2015. http://doi.org/10.1128/MCB.01603-12
    Keywords: Human DEAD Box Helicase 3 Couples; IκB Kinase ε; Interferon; Regulatory Factor 3 Activation; DEAD box protein 3 (DDX3); HIV; hepatitis C virus;
    Academic Unit: Faculty of Science and Engineering > Biology
    Faculty of Science and Engineering > Research Institutes > Institute of Immunology
    Item ID: 6917
    Identification Number: https://doi.org/10.1128/MCB.01603-12
    Depositing User: Martina Schroeder
    Date Deposited: 22 Jan 2016 16:18
    Journal or Publication Title: Molecular and Cellular Biology
    Publisher: American Society for Microbiology
    Refereed: Yes
    Funders: Health Research Board (HRB), Science Foundation Ireland (SFI)
    URI:

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