MAP kinase-activated protein kinases 2 and 3 are required for influenza A virus propagation and act via inhibition of PKR
MAP kinase-activated protein kinases 2 and 3 are required for influenza A virus propagation and act via inhibition of PKR
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DOI：
10.1096/fj.10-158766
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发表时间：
2010-10-01
期刊：
影响因子：
4.8
通讯作者：
Ludwig, Stephan
中科院分区：
文献类型：
--
作者：
Luig, Christina;Koether, Katharina;Ludwig, Stephan
流感病毒必须克服I型干扰素诱导的抗病毒反应才能在靶细胞中成功繁殖。干扰素诱导的主要抗病毒因子是蛋白激酶R (PKR)，它被dsRNA进一步激活并磷酸化真核起始因子2 （eIF2 α）。这导致抑制蛋白质翻译，从而限制病毒复制。在这里，我们描述了一种新的机制，通过它甲型流感病毒逃避PKR的抗病毒作用。我们证明了丝裂原活化蛋白激酶活化蛋白激酶（MAPKAPKs） MK2和MK3在病毒感染时被激活，并且在其活性形式下，直接与PKR p88抑制剂的抑制因子（rIPK）相互作用。这导致由p88（rIPK）、PKR抑制剂p58（IPK）和PKR本身组成的四聚体蛋白复合物的募集，并最终导致激酶的抑制。mk对流感病毒传播的重要性进一步得到强调，因为在MK2或MK3基因基因缺陷的细胞中，以及在高度增殖的肿瘤细胞中，mk的表达被特异性小干扰RNA减少，病毒后代减少。因此，mk的敲低导致PKR及其底物eIF2 α的磷酸化增强。-Luig， C, Kother， K, Dudek, s.e, Gaestel， M., Hiscott， J., Wixler， V., Ludwig， S. MAP激酶激活蛋白激酶2和3是甲型流感病毒传播所必需的，并通过抑制PKR起作用。中国生物医学工程学报，2009,33(4):444 - 444。www.fasebj.org
Influenza viruses have to overcome the type I interferon induced antiviral response to successfully propagate in target cells. A major antiviral factor induced by interferons is the protein kinase R (PKR) that is further activated by dsRNA and phosphorylates the eukaryotic initiation factor 2 (eIF2 alpha). This results in inhibition of protein translation thereby limiting viral replication. Here we describe a novel mechanism by which influenza A viruses escape the antiviral action of PKR. We demonstrate that the mitogen-activated protein kinase-activated protein kinases (MAPKAPKs) MK2 and MK3 are activated on virus infection and, in their active form, directly interact with the repressor of the inhibitor of PKR p88(rIPK). This leads to recruitment of a tetrameric protein complex consisting of p88(rIPK), the inhibitor of PKR p58(IPK) and PKR itself, and finally results in inhibition of the kinase. The importance of MKs for influenza virus propagation was further underscored by demonstrating reduced viral progeny in cells genetically deficient in MK2 or MK3 genes as well as in highly proliferating tumor cells, in which expression of MKs was diminished by specific small interfering RNA. Accordingly, knockdown of MKs resulted in enhanced phosphorylation of PKR and its substrate eIF2 alpha.-Luig, C., Kother, K., Dudek, S. E., Gaestel, M., Hiscott, J., Wixler, V., Ludwig, S. MAP kinase-activated protein kinases 2 and 3 are required for influenza A virus propagation and act via inhibition of PKR. FASEB J. 24, 4068-4077 (2010). www.fasebj.org