title: Human DEAD box helicase 3 couples IκB kinase ε to interferon regulatory factor 3 activation.
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.
authors.affiliation: National University of Ireland Maynooth, Maynooth, County Kildare, Ireland.
authors.forename: Lili
authors.initials: L
authors.lastname: Gu
authors.forename: Anthony
authors.initials: A
authors.lastname: Fullam
authors.forename: Ruth
authors.initials: R
authors.lastname: Brennan
authors.forename: Martina
authors.initials: M
authors.lastname: Schröder
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D015870:Gene Expression; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry / Q000378:metabolism*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000737:chemistry; D010449:Peptide Mapping; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D015533:Transcriptional Activation
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D010446:Peptide Fragments; D016899:Interferon-beta; D051550:I-kappa B Kinase; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases