Novel Functions of IFI44L as a Feedback Regulator of Host Antiviral Responses
Novel Functions of IFI44L as a Feedback Regulator of Host Antiviral Responses
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DOI：
10.1128/jvi.01159-19
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发表时间：
2019-11-01
影响因子：
5.4
通讯作者：
Topham, David J.
中科院分区：
文献类型：
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作者：
DeDiego, Marta L.;Martinez-Sobrido, Luis;Topham, David J.
我们描述了一种新的功能干扰素（IFN）诱导的蛋白44样（IFI 44 L）基因在负调节先天性免疫反应后诱导病毒感染。此外，我们表明IFI 44 L表达的减少会损害病毒的产生，并且IFI 44 L表达会负调节双链RNA类似物（dsRNA）或IFN处理诱导的抗病毒状态。该机制可能涉及IFI 44 L与细胞FK 506结合蛋白5（FKBP 5）的相互作用，FKBP 5又与I型和III型IFN应答所必需的激酶相互作用，如核因子κ B（I kappa B）激酶α（IKK α）、IKK β和IKK β的抑制剂。因此，IFI 44 L与FKBP 5的结合降低了干扰素调节因子3（IRF-3）介导的IKK β和IKK β分别介导的和核因子κ-B（NF-κ B）抑制剂（I κ B α）介导的磷酸化。根据这些结果，IFI 44 L是治疗与过度IFN水平和/或促炎反应相关的疾病以及减少病毒复制的良好靶点。在这里，我们描述了一个全新的功能IFI 44 L在负性调节先天免疫反应诱导病毒感染后。此外，我们表明，减少IFI 44 L的表达损害病毒的生产和IFI 44 L的表达负调制的dsRNA的类似物或IFN治疗诱导的抗病毒状态。IFI 44 L与细胞蛋白FKBP 5结合，FKBP 5又与I型和III型IFN诱导和信号传导所必需的激酶相互作用，例如激酶IKK α、IKK β和IKK β。IFI 44 L与FKBP 5的结合降低了分别由IKK β和IKK β介导的IRF-3和IKB α的磷酸化，这为IFI 44 L在负调节IFN应答中的功能提供了解释。因此，IFI 44 L是减少病毒复制的候选靶标。
We describe a novel function for the interferon (IFN)-induced protein 44-like (IFI44L) gene in negatively modulating innate immune responses induced after virus infections. Furthermore, we show that decreasing IFI44L expression impairs virus production and that IFI44L expression negatively modulates the antiviral state induced by an analog of double-stranded RNA (dsRNA) or by IFN treatment. The mechanism likely involves the interaction of IFI44L with cellular FK506-binding protein 5 (FKBP5), which in turn interacts with kinases essential for type I and III IFN responses, such as inhibitor of nuclear factor kappa B (I kappa B) kinase alpha (IKK alpha), IKK beta, and IKK epsilon. Consequently, binding of IFI44L to FKBP5 decreased interferon regulatory factor 3 (IRF-3)-mediated and nuclear factor kappa-B (NF-kappa B) inhibitor (I kappa B alpha)-mediated phosphorylation by IKK epsilon and IKK beta respectively. According to these results, IFI44L is a good target for treatment of diseases associated with excessive IFN levels and/or proinflammatory responses and for reduction of viral replication.IMPORTANCE Excessive innate immune responses can be deleterious for the host, and therefore, negative feedback is needed. Here, we describe a completely novel function for IFI44L in negatively modulating innate immune responses induced after virus infections. In addition, we show that decreasing IFI44L expression impairs virus production and that IFI44L expression negatively modulates the antiviral state induced by an analog of dsRNA or by IFN treatment. IFI44L binds to the cellular protein FKBP5, which in turn interacts with kinases essential for type I and III IFN induction and signaling, such as the kinases IKK alpha, 1KK beta, and IKK epsilon. IFI44L binding to FKBP5 decreased the phosphorylation of IRF-3 and IKB alpha mediated by IKK epsilon and IKK beta, respectively, providing an explanation for the function of IFI44L in negatively modulating IFN responses. Therefore, IFI44L is a candidate target for reducing virus replication.