微小 RNA miR-526a 受肠道病毒下调可抑制 RIG-I 依赖性先天免疫反应。
Downregulation of microRNA miR-526a by enterovirus inhibits RIG-I-dependent innate immune response.
机构信息
Beijing Institute of Biotechnology, Beijing, China Institute of Health Science, School of Life Sciences, AnHui University, Hefei, Anhui, China.
Beijing Institute of Biotechnology, Beijing, China.
出版信息
J Virol. 2014 Oct;88(19):11356-68. doi: 10.1128/JVI.01400-14. Epub 2014 Jul 23.
UNLABELLED
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.
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视黄酸诱导基因 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，以抵抗病毒感染。尽管已经表明圆柱瘤病（CYLD）通过从 RIG-I 上去除 K-63 连接的多泛素来负调控先天抗病毒反应，但它的表达调控及其潜在的调控机制仍不完全清楚。在这里，我们表明 RIG-I 的活性受到 miR-526a 介导的 CYLD 表达抑制的调节。我们发现，病毒感染通过干扰素调节因子（IRF）依赖性机制特异性地上调巨噬细胞中 miR-526a 的表达。反过来，miR-526a 通过抑制 CYLD 的表达正向调节病毒触发的 I 型干扰素（IFN-I）的产生，从而抑制病毒复制，其潜在机制是通过抑制 CYLD 的表达增强 RIG-I 的 K63 连接的泛素化。值得注意的是，肠道病毒 71（EV71）3C 蛋白阻断病毒诱导的 miR-526a 上调和 CYLD 下调，而外源性 miR-526a 表达抑制 EV71 病毒的复制。本研究的综合结果表明，miR-526a 通过调节 RIG-I 活性在 RNA 病毒感染期间提供了一种新的机制，并提出了 EV71 控制的先天免疫反应逃避的一种新机制。
意义
RNA 病毒感染通过 IRF 依赖性途径在上调巨噬细胞中 miR-526a 的表达。反过来，miR-526a 通过抑制 CYLD 的表达正向调节病毒触发的 I 型 IFN 的产生，并抑制病毒复制，其潜在机制是通过抑制 CYLD 的表达增强 RIG-I 的 K-63 连接的泛素化。值得注意的是，肠道病毒 71（EV71）3C 蛋白阻断病毒诱导的 miR-526a 上调和 CYLD 下调；过表达 miR-526a 的细胞对 EV71 感染具有高度抗性。本研究的综合结果表明，miR-526a 通过调节 RIG-I 活性在 RNA 病毒感染期间提供了一种新的机制，并提出了 EV71 控制的先天免疫反应逃避的一种新机制。
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