High-Throughput Profiling of Alpha Interferon- and Interleukin-28B-Regulated MicroRNAs and Identification of let-7s with Anti-Hepatitis C Virus Activity by Targeting IGF2BP1
High-Throughput Profiling of Alpha Interferon- and Interleukin-28B-Regulated MicroRNAs and Identification of let-7s with Anti-Hepatitis C Virus Activity by Targeting IGF2BP1
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通过靶向 IGF2BP1，对α干扰素和白细胞介素 28B 调节的 MicroRNA 进行高通量分析，并鉴定具有抗丙型肝炎病毒活性的 let-7
DOI：
10.1128/jvi.00802-13
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发表时间：
2013-09-01
影响因子：
5.4
通讯作者：
Yang, Wei
中科院分区：
文献类型：
--
作者：
Cheng, Min;Si, Youhui;Yang, Wei
摘要丙型肝炎病毒（HCV）感染是导致严重肝病的主要原因。干扰素（IFN）/利巴韦林治疗仍然是大多数国家HCV感染的标准治疗方案。干扰素刺激的基因被认为有助于抗病毒作用。然而，新的证据表明，microRNAs（miRNAs），一类非编码小RNA，参与控制病毒感染。在这里，我们系统地分析了一组750种miRNA在α干扰素（IFN-α）和白细胞介素-28 B（IL-28 B）治疗后的肝细胞表达。使用细胞培养衍生的HCV在体外评估差异表达的miRNA的抗HCV活性。结果表明，let-7 b通过抑制HCV在人肝癌细胞中的复制和病毒蛋白翻译而具有显著的抗HCV作用。特别是，我们发现let-7 b的抑制减弱了IFN-α和IL-28 B的抗HCV作用。此外，我们表明宿主因子胰岛素样生长因子2 mRNA结合蛋白1（IGF 2BP 1）是let-7 b的靶点。IGF 2BP 1是HCV复制所必需的，IFN-α和IL-28 B可下调IGF 2BP 1的表达。let-7 b野生型种子区的缺失消除了其抗病毒活性。最后，我们证明了其他let-7家族miRNAs能够抑制HCV和IGF 2BP 1的表达。总之，我们提供了一个由I型和III型IFN调控的宿主miRNA的例子，其通过靶向宿主靶标来抑制HCV复制和感染性。这些结果突出了miRNAs在宿主抗病毒免疫应答中的重要作用，并为抗HCV治疗提供了新的候选者。
ABSTRACT Hepatitis C virus (HCV) infection is a major cause of severe liver disease. Interferon (IFN)/ribavirin treatment remains the standard therapeutic regimen for HCV infection in most countries. IFN-stimulated genes are believed to contribute to antiviral effects. However, emerging evidence suggests that microRNAs (miRNAs), a class of noncoding small RNAs, are involved in the control of viral infection. Here, we systematically profiled the hepatocyte expression of a set of 750 miRNAs in response to alpha interferon (IFN-α) and interleukin-28B (IL-28B) treatments. The anti-HCV activity of differentially expressed miRNAs was evaluated using cell culture-derived HCV in vitro. The results demonstrate that let-7b had a significant anti-HCV effect by inhibiting HCV replication and viral protein translation in human hepatoma cells. In particular, we show that the inhibition of let-7b attenuated the anti-HCV effects of IFN-α and IL-28B. Furthermore, we show that the host factor insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is a target of let-7b. IGF2BP1 was required for HCV replication, and its expression was downregulated by IFN-α and IL-28B. Deletion of the wild-type seed region of let-7b abolished its antiviral activity. Finally, we demonstrate that other let-7 family miRNAs were able to inhibit HCV and to suppress IGF2BP1 expression. In conclusion, we provide an example of a host miRNA regulated by type I and type III IFNs that inhibits HCV replication and infectivity by targeting host targets. These results highlight the important role of miRNAs in the host antiviral immune response and provide a novel candidate for anti-HCV therapy.