DDX3 directly facilitates IKKα activation and regulates downstream signalling pathways
DDX3 directly facilitates IKKα activation and regulates downstream signalling pathways
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DOI：
10.1042/bcj20180163
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发表时间：
2018-11-30
影响因子：
4.1
通讯作者：
Schroeder, Martina
中科院分区：
文献类型：
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作者：
Fullam, Anthony;Gu, Lili;Schroeder, Martina
DDX 3是一种DEAD盒RNA解旋酶，我们和其他人以前曾参与导致I型干扰素（IFN）诱导的抗病毒免疫信号通路。我们以前证明，它直接与激酶IKK β（I κ B激酶β）相互作用，增强其激活，然后促进IKK β对转录因子IRF 3的磷酸化。然而，TLR 7/9（Toll样受体7/9）介导的途径，最生理相关的IFN诱导途径之一，独立于IKK β或相关激酶TBK 1（TANK结合激酶1）进行。该途径通过激酶NIK（NF-κ B诱导激酶）和IKK α诱导I型IFN产生，并且当浆细胞样树突状细胞感知病毒核酸时被激活。在本研究中，我们证明DDX 3也直接与IKK α相互作用，并增强其自身磷酸化和激活。DDX 3表达的调节因此影响NIK/IKK α介导的IRF 7磷酸化和I型干扰素的诱导。此外，替代性NF-κ B（核因子-κ B）激活（NIK和IKK α调节的另一种途径）也在DDX 3敲减细胞中下调。这大大拓宽了DDX 3在先天免疫信号传导中的作用，使其途径超出了TBK 1/IKK β和IFN诱导。这些通路的失调与疾病状态有关，因此，我们的研究可能涉及DDX 3作为其治疗操作的潜在靶点。
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 IKK epsilon (I kappa B kinase epsilon), enhances it activation, and then facilitates phosphorylation of the transcription factor IRF3 by IKK epsilon. However, the TLR7/9 (Toll-like receptor 7/9)-mediated pathway, one of the most physiologically relevant IFN induction pathways, proceeds independently of IKK epsilon or the related kinase TBK1 (TANK-binding kinase 1). This pathway induces type I IFN production via the kinases NIK (NF-kappa B-inducing kinase) and IKK alpha and is activated when plasmacytoid dendritic cells sense viral nucleic acids. In the present study, we demonstrate that DDX3 also directly interacts with IKK alpha and enhances its autophosphorylation and -activation. Modulation of DDX3 expression consequently affected NIK/IKK alpha-mediated IRF7 phosphorylation and induction of type I interferons. In addition, alternative NF-kappa B (nuclear factor-kappa B) activation, another pathway regulated by NIK and IKK alpha, was also down-regulated in DDX3 knockdown cells. This substantially broadens the effects of DDX3 in innate immune signalling to pathways beyond TBK1/IKK epsilon 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.