Since ZIKV was first detected at Uganda in 1947 and, serious outbreaks have globally occurred in the Yap Island, the French Polynesia and Brazil. Even though the number of infection and spread of ZIKV have sharply rise, the pathogenesis or replication mechanisms ZIKV have not been well studied. Zika virus (ZIKV) is recently highlighted Flavivirus, a mosquito born emerging virus causing microcephaly and the Guillain-Barre syndrome in fetuses and adults, respectively. ZIKV polyprotein consists of three structural proteins named C, prM and E and seven nonstructural proteins named NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5 in 11-kb single-stranded positive sense RNA genome. The function of individual ZIKV genes on the host innate immune responses have been barely studied. In this study, we investigated the modulations of the NF-κB promoter activity related by the MDA5/RIG-I signaling pathway. In the results, two nonstructural proteins, NS2A and NS4A, dramatically suppressed the NF-κB promoter activity by inhibiting signaling factors on MDA5/RIG-I signaling pathway related to activation of NF-κB. Interestingly, NS2A suppressed all components of MDA5/RIG-I signaling pathway, but NS4A inhibited most signaling molecules, except IKKε and IRF3-5D. In addition, both NS2A and NS4A down-regulated MDA5 related NF-κB promoter activity in dose-dependent manner. Taken together, our results presented that NS2A and NS4A critically antagonize MDA5/RIG-I-mediated NF-κB production and those proteins may seem to be controlled in different mechanisms. This study could help understand the mechanisms how ZIKV controls innate immune responses and may be provided for development of ZIKV-specific medicines.

中文翻译：

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寨卡病毒 NS2A 和 NS4A 下调活化 B 细胞核因子 Kappa-轻链增强子的启动子活性。

自 1947 年在乌干达首次发现寨卡病毒以来，雅浦岛、法属波利尼西亚和巴西在全球范围内爆发了严重疫情。尽管 ZIKV 的感染和传播数量急剧上升，但 ZIKV 的发病机制或复制机制尚未得到很好的研究。寨卡病毒 (ZIKV) 最近被强调为黄病毒，这是一种蚊子出生的新兴病毒，分别导致胎儿和成人出现小头畸形和吉兰-巴利综合征。ZIKV 多蛋白由 11-kb 单链正链 RNA 基因组中的三种结构蛋白 C、prM 和 E 和七种非结构蛋白 NS1、NS2A、NS2B、NS3、NS4A、NS4B 和 NS5 组成。几乎没有研究过个体 ZIKV 基因对宿主先天免疫反应的作用。在这项研究中，我们研究了与 MDA5/RIG-I 信号通路相关的 NF-κB 启动子活性的调节。在结果中，两种非结构蛋白 NS2A 和 NS4A 通过抑制与 NF-κB 激活相关的 MDA5/RIG-I 信号通路上的信号因子，显着抑制了 NF-κB 启动子活性。有趣的是，NS2A 抑制了 MDA5/RIG-I 信号通路的所有成分，但 NS4A 抑制了除 IKKε 和 IRF3-5D 之外的大多数信号分子。此外，NS2A 和 NS4A 均以剂量依赖的方式下调 MDA5 相关的 NF-κB 启动子活性。总之，我们的结果表明 NS2A 和 NS4A 严重拮抗 MDA5/RIG-I 介导的 NF-κB 产生，并且这些蛋白质似乎以不同的机制受到控制。