Human DEAD Box Helicase 3 Couples IκB Kinase ε to Interferon Regulatory Factor 3 Activation
Human DEAD Box Helicase 3 Couples IκB Kinase ε to Interferon Regulatory Factor 3 Activation
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DOI：
10.1128/mcb.01603-12
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发表时间：
2013-05-01
影响因子：
5.3
通讯作者：
Schroeder, Martina
中科院分区：
文献类型：
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作者：
Gu, Lili;Fullam, Anthony;Schroeder, Martina
人类死亡盒蛋白3（DDX3）参与了不同的基因表达过程。有趣的是，DDX3是HIV和丙型肝炎病毒（HCV）复制所必需的重要宿主因子，因此被认为是潜在的药物靶标。另一方面，DDX 3与I κ B激酶I（IKK I）和TANK结合激酶1（TBK 1）相互作用，并有助于诱导抗病毒I型干扰素（IFN）。然而，DDX3促进IFN诱导的分子机制仍不清楚。在这里，我们表明，DDX3介导的干扰素调节因子3（IRF3）的激酶IKK β的磷酸化。DDX3直接与IKK β相互作用并增强其自身磷酸化和激活。然后IKK β磷酸化DDX3 N末端的几个丝氨酸残基。DDX3在丝氨酸102（S102）处的磷酸化是IRF 3募集到DDX3所必需的，从而促进其通过IKK β的磷酸化。S102突变为丙氨酸后，DDX3与IRF 3之间的相互作用被破坏，但DDX3与IKK β之间的相互作用未被破坏。S102A突变未能增强ifnb启动子激活，表明DDX3-IRF3相互作用对这种作用至关重要。我们的数据暗示DDX3作为支架适配器，直接促进IKK β对IRF3的磷酸化。DDX3因此可能参与IRF3的通路特异性激活。
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 I kappa B kinase epsilon (IKK epsilon) 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 IKK epsilon. DDX3 directly interacts with IKK epsilon and enhances its autophosphorylation and activation. IKK epsilon 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 IKK epsilon. Mutation of S102 to alanine disrupted the interaction between DDX3 and IRF3 but not that between DDX3 and IKK epsilon. 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 IKK epsilon. DDX3 might thus be involved in pathway-specific activation of IRF3.