MicroRNA-548 down-regulates host antiviral response via direct targeting of IFN-λ1
MicroRNA-548 down-regulates host antiviral response via direct targeting of IFN-λ1
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DOI：
10.1007/s13238-012-2081-y
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发表时间：
2013-02-01
期刊：
影响因子：
21.1
通讯作者：
Zhu, Ying
中科院分区：
文献类型：
--
作者：
Li, Yongkui;Xie, Jiajia;Zhu, Ying
干扰素（IFN）介导的途径是细胞对病毒感染的反应的重要组成部分。III型IFN，包括IFN-λ 1、2和3，通过不同的受体复合物介导与I型IFN类似的抗病毒应答。IFN-λ 1比其他两个成员更有效。IFN-λ 1的转录需要IRF 3/7和核因子-κ B（NF-κ B）的活化，类似于I型IFN的转录机制。使用报告基因分析，我们发现病毒感染诱导IFN-λ 1启动子活性和3 '-非翻译区（UTR）的活性，表明IFN-λ 1表达也在转录后水平上受到调节。在用microRNA（miRNA）预测程序和3 'UTR靶向位点测定分析后，鉴定了miRNA-548家族，包括miR-548 b-5 p、miR-548 c-5 p、miR-548 i、miR-548 j和miR-548 n，以靶向IFN-λ 1的3' UTR。进一步的研究表明，miRNA-548模拟下调IFN-λ 1的表达。相反，它们的抑制剂，互补RNA，增强了IFN-λ 1和IFN刺激基因的表达。此外，miRNA-548模拟物促进肠道病毒71（EV 71）和水泡性口炎病毒（VSV）的感染，而其抑制剂显著抑制EV 71和VSV的复制。内源性miRNA-548水平在病毒感染期间受到抑制。总之，我们的研究结果表明，miRNA-548通过直接靶向IFN-λ 1来调节宿主的抗病毒反应，这可能为抗病毒治疗提供潜在的候选者。
Interferon (IFN)-mediated pathways are a crucial part of the cellular response against viral infection. Type III IFNs, which include IFN-lambda 1, 2 and 3, mediate antiviral responses similar to Type I IFNs via a distinct receptor complex. IFN-lambda 1 is more effective than the other two members. Transcription of IFN-lambda 1 requires activation of IRF3/7 and nuclear factor-kappa B (NF-kappa B), similar to the transcriptional mechanism of Type I IFNs. Using reporter assays, we discovered that viral infection induced both IFN-lambda 1 promoter activity and that of the 3'-untranslated region (UTR), indicating that IFN-lambda 1 expression is also regulated at the post-transcriptional level. After analysis with microRNA (miRNA) prediction programs and 3'UTR targeting site assays, the miRNA-548 family, including miR-548b-5p, miR-548c-5p, miR-548i, miR-548j, and miR-548n, was identified to target the 3'UTR of IFN-lambda 1. Further study demonstrated that miRNA-548 mimics down-regulated the expression of IFN-lambda 1. In contrast, their inhibitors, the complementary RNAs, enhanced the expression of IFN-lambda 1 and IFN-stimulated genes. Furthermore, miRNA-548 mimics promoted infection by enterovirus-71 (EV71) and vesicular stomatitis virus (VSV), whereas their inhibitors significantly suppressed the replication of EV71 and VSV. Endogenous miRNA-548 levels were suppressed during viral infection. In conclusion, our results suggest that miRNA-548 regulates host antiviral response via direct targeting of IFN-lambda 1, which may offer a potential candidate for antiviral therapy.