Human DEAD box helicase 3 couples IkappaB kinase epsilon to interferon regulatory factor 3 activation.
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Gu L, Fullam A, Brennan R, Schroder M
Human DEAD box helicase 3 couples IkappaB kinase epsilon to interferon regulatory factor 3 activation.
Mol Cell Biol. 2013 May;33(10):2004-15. doi: 10.1128/MCB.01603-12. Epub 2013 Mar 11.
- PubMed ID
- 23478265 [ View in PubMed]
- 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 IkappaB kinase epsilon (IKKepsilon) 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 IKKepsilon. DDX3 directly interacts with IKKepsilon and enhances its autophosphorylation and activation. IKKepsilon 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 IKKepsilon. Mutation of S102 to alanine disrupted the interaction between DDX3 and IRF3 but not that between DDX3 and IKKepsilon. 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 IKKepsilon. DDX3 might thus be involved in pathway-specific activation of IRF3.