MicroRNA-206 inhibits influenza A virus replication by targeting tankyrase 2.
MicroRNA-206 inhibits influenza A virus replication by targeting tankyrase 2.
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DOI：
10.1111/cmi.13281
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发表时间：
2021-03
影响因子：
3.4
通讯作者：
Liu L
中科院分区：
文献类型：
--
作者：
Bamunuarachchi G;Yang X;Huang C;Liang Y;Guo Y;Liu L
由于甲型流感病毒（IAV）的频繁突变，其对靶向流感病毒蛋白的抗病毒药物产生耐药性。人们对靶向病毒复制所需的宿主细胞蛋白的抗病毒剂越来越感兴趣。端锚聚合酶（TNKS）具有聚（ADP-核糖）聚合酶活性，并且是许多宿主蛋白质的负调节剂。本研究的目的是研究TNKS 2在IAV感染中的作用，鉴定靶向TNKS 2的microRNA，并了解其相关机制。我们发现，TNKS 2表达升高，在人类肺上皮细胞和小鼠肺在IAV感染。通过RNA干扰敲低TNKS 2降低了病毒复制。使用计算方法和3 '-非翻译区（3'-UTR）报告基因测定，我们鉴定了miR-206作为靶向TNKS 2的micro-RNA。miR-206的过表达降低了细胞培养物中的病毒蛋白水平和病毒产生。miR-206对IAV复制的影响不依赖于毒株。miR-206激活JNK/c-Jun信号传导，诱导I型干扰素表达并增强Stat信号传导。最后，将表达miR-206的腺病毒递送到用IAV攻击的小鼠的肺中增加了I型干扰素应答，抑制了肺中的病毒载量并增加了存活率。我们的研究结果表明，miR-206通过靶向TNKS 2并随后激活抗病毒状态而具有抗流感活性。
Due to the frequent mutations, influenza A virus (IAV) becomes resistant to anti-viral drugs targeting influenza viral proteins. There are increasing interests in anti-viral agents that target host cellular proteins required for virus replication. Tankyrase (TNKS) has poly (ADP-ribose) polymerase activity and is a negative regulator of many host proteins. The objectives of this study are to study the role of TNKS2 in IAV infection, identify the microRNAs targeting TNKS2, and to understand the mechanisms involved. We found that TNKS2 expression was elevated in human lung epithelial cells and mouse lungs during IAV infection. Knock-down of TNKS2 by RNA interference reduced viral replication. Using a computation approach and 3’-untranslation regions (3’-UTR) reporter assay, we identified miR-206 as the micro-RNA that targeted TNKS2. Overexpression of miR-206 reduced viral protein levels and virus production in cell culture. The effect of miR-206 on IAV replication was strain-independent. miR-206 activated JNK/c-Jun signalling, induced type I interferon expression and enhanced Stat signalling. Finally, the delivery of an adenovirus expressing miR-206 into the lung of mice challenged with IAV increased type I interferon response, suppressed viral load in the lungs and increased survival. Our results indicate that miR-206 has anti-influenza activity by targeting TNKS2 and subsequently activating the anti-viral sate.
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