Downregulation of MicroRNA miR-526a by Enterovirus Inhibits RIG-I-Dependent Innate Immune Response
Downregulation of MicroRNA miR-526a by Enterovirus Inhibits RIG-I-Dependent Innate Immune Response
复制标题
DOI：
10.1128/jvi.01400-14
复制
发表时间：
2014-07
影响因子：
5.4
通讯作者：
Changzhi Xu;Xiang He;Zirui Zheng;Zhe Zhang;Congwen Wei;K. Guan;L. Hou;Buchang Zhang;Lin Zhu-Li
中科院分区：
文献类型：
--
作者：
Changzhi Xu;Xiang He;Zirui Zheng;Zhe Zhang;Congwen Wei;K. Guan;L. Hou;Buchang Zhang;Lin Zhu-Li
维甲酸诱导基因I （RIG-I）是一种细胞内RNA病毒传感器，可诱导I型干扰素介导的宿主保护性先天免疫对抗病毒感染。尽管圆柱状瘤病（CYLD）已被证明通过从rig - 1中去除k -63连接的多泛素来负性调节先天抗病毒反应，但其表达的调控及其潜在的调控机制仍不完全清楚。在这里，我们发现RIG-I活性是通过microRNA miR-526a介导的CYLD表达抑制来调节的。我们发现病毒感染通过干扰素调节因子（IRF）依赖机制特异性上调巨噬细胞中miR-526a的表达。反过来，miR-526a正调控病毒触发的I型干扰素（IFN-I）的产生，从而抑制病毒复制，其潜在机制是miR-526a通过抑制CYLD的表达增强RIG-I k63连接的泛素化。值得注意的是，病毒诱导的miR-526a上调和CYLD下调被肠病毒71 (EV71) 3C蛋白阻断，而异位miR-526a表达抑制EV71病毒的复制。本研究的总体结果提示了miR-526a在RNA病毒感染过程中调控RIG-I活性的新机制，并提示了逃避EV71控制的先天免疫反应的新机制。RNA病毒感染通过irf依赖性途径上调巨噬细胞中miR-526a的表达。反过来，miR-526a正调控病毒触发的I型IFN的产生并抑制病毒复制，其潜在机制是miR-526a通过抑制CYLD的表达增强RIG-I K-63的泛素化。值得注意的是，病毒诱导的miR-526a上调和CYLD下调被肠病毒71 (EV71) 3C蛋白阻断；过表达miR-526a的细胞对EV71感染具有高度抗性。本研究的总体结果提示了miR-526a在RNA病毒感染过程中调控RIG-I活性的新机制，并提出了逃避EV71控制的先天免疫反应的新机制。
ABSTRACT Retinoic acid-inducible gene I (RIG-I) is an intracellular RNA virus sensor that induces type I interferon-mediated host-protective innate immunity against viral infection. Although cylindromatosis (CYLD) has been shown to negatively regulate innate antiviral response by removing K-63-linked polyubiquitin from RIG-I, the regulation of its expression and the underlying regulatory mechanisms are still incompletely understood. Here we show that RIG-I activity is regulated by inhibition of CYLD expression mediated by the microRNA miR-526a. We found that viral infection specifically upregulates miR-526a expression in macrophages via interferon regulatory factor (IRF)-dependent mechanisms. In turn, miR-526a positively regulates virus-triggered type I interferon (IFN-I) production, thus suppressing viral replication, the underlying mechanism of which is the enhancement of RIG-I K63-linked ubiquitination by miR-526a via suppression of the expression of CYLD. Remarkably, virus-induced miR-526a upregulation and CYLD downregulation are blocked by enterovirus 71 (EV71) 3C protein, while ectopic miR-526a expression inhibits the replication of EV71 virus. The collective results of this study suggest a novel mechanism of the regulation of RIG-I activity during RNA virus infection by miR-526a and suggest a novel mechanism for the evasion of the innate immune response controlled by EV71. IMPORTANCE RNA virus infection upregulates the expression of miR-526a in macrophages through IRF-dependent pathways. In turn, miR-526a positively regulates virus-triggered type I IFN production and inhibits viral replication, the underlying mechanism of which is the enhancement of RIG-I K-63 ubiquitination by miR-526a via suppression of the expression of CYLD. Remarkably, virus-induced miR-526a upregulation and CYLD downregulation are blocked by enterovirus 71 (EV71) 3C protein; cells with overexpressed miR-526a were highly resistant to EV71 infection. The collective results of this study suggest a novel mechanism of the regulation of RIG-I activity during RNA virus infection by miR-526a and propose a novel mechanism for the evasion of the innate immune response controlled by EV71.