DDX24 negatively regulates cytosolic RNA-mediated innate immune signaling.
DDX24 negatively regulates cytosolic RNA-mediated innate immune signaling.
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DOI：
10.1371/journal.ppat.1003721
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发表时间：
2013-10
期刊：
影响因子：
6.7
通讯作者：
Barber GN
中科院分区：
文献类型：
--
作者：
Ma Z;Moore R;Xu X;Barber GN
RIG-I 样受体 (RLR) 感知胞质病毒 RNA，短暂激活 I 型 IFN 的产生。在此，我们报道 I 型 IFN 诱导型 DExD/H 解旋酶 DDX24 对 RLR 功能发挥负调节作用。 DDX24 的表达特异性抑制 RLR 活性，而 DDX24 缺失会导致胚胎致死，增强胞质 RNA 介导的先天信号传导并促进 RNA 病毒复制。 DDX24 优先与 RNA 而不是 DNA 物质结合，并通过与接头蛋白 FADD 和 RIP1 结合来影响信号传导。这些事件优先阻碍 IRF7 活性，IRF7 是 I 型 IFN 产生的重要转录因子。我们的数据为 DDX24 提供了一种新功能，并有助于解释先天免疫基因调控以及可能进一步深入了解炎症性疾病原因的机制。先天免疫是宿主针对病毒感染的第一个也是最快速的防御。 RNA病毒在宿主细胞中复制过程中产生的病毒RNA可以通过RIG-I样受体（RLR）识别，瞬时产生I型干扰素，进一步诱导丰富的干扰素刺激基因（ISG）清除病毒感染。然而，不受控制的先天免疫反应会导致对宿主有害的炎症性疾病。因此，平衡的先天免疫反应对于维持宿主的体内平衡至关重要。因此，RLR 信号传导受到正调节因子和负调节因子的严格调节。 DDX24 是本研究中报道的一种解旋酶，是一种对 RLR 依赖性信号传导发挥抑制作用的 ISG。 DDX24 劫持了宿主细胞中的接头蛋白 FADD 和 RIP1，以抑制病毒 RNA 依赖性干扰素的产生，并促进 RNA 病毒在某些细胞中的复制。此外，DDX24 缺陷小鼠胚胎表现出早期胚胎致死性，表明该解旋酶除了调节 RLR 信号传导之外还发挥着重要作用。总之，我们的结果阐明了 DDX24 在 RLR 依赖性信号传导中的作用，并可能揭示先天免疫基因调控。
RIG-I-Like Receptors (RLRs) sense cytosolic viral RNA to transiently activate type I IFN production. Here, we report that a type I IFN inducible DExD/H helicase, DDX24, exerts a negative-regulatory effect on RLR function. Expression of DDX24 specifically suppressed RLR activity, while DDX24 loss, which caused embryonic lethality, augmented cytosolic RNA-mediated innate signaling and facilitated RNA virus replication. DDX24 preferentially bound to RNA rather than DNA species and influenced signaling by associating with adaptor proteins FADD and RIP1. These events preferentially impeded IRF7 activity, an essential transcription factor for type I IFN production. Our data provide a new function for DDX24 and help explain innate immune gene regulation, mechanisms that may additionally provide insight into the causes of inflammatory disease. Innate immunity is the first and most rapid host defense against virus infection. Viral RNAs, which are generated during RNA virus replication in host cells, can be recognized through RIG-I-Like Receptors (RLRs) to transiently produce type I interferon, which further induce abundant interferon stimulated genes (ISGs) to clear viral infection. However, uncontrolled innate immune responses cause inflammatory diseases that are detrimental to the host. Therefore, a balanced innate immune response is critical to maintain homeostasis of the host. Thus, RLR signaling is tightly regulated by both positive and negative regulators. DDX24, a helicase reported in this study, is an ISG that exerts an inhibitory effect on RLR dependent signaling. DDX24 hijacked adaptor proteins FADD and RIP1 in host cells to suppress viral RNA dependent interferon production and facilitated RNA virus replication in certain cells. Moreover, DDX24 deficient mouse embryos exerted early embryonic lethality, suggesting an important role for this helicase, perhaps in addition to regulating RLR signaling. In all, our results elucidate the role of DDX24 in RLR dependent signaling, and may shed light on innate immune gene regulation.
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