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首页> 外文期刊>Journal of Molecular Biology >Viral dsRNA inhibitors prevent self-association and autophosphorylation of PKR
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Viral dsRNA inhibitors prevent self-association and autophosphorylation of PKR

机译：病毒dsRNA抑制剂可防止PKR的自缔合和自磷酸化

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摘要

Host response to viral RNA genomes and replication products represents an effective strategy to combat viral invasion. PKR is a Ser/Thr protein kinase that binds to double-stranded (ds)RNA, autophosphorylates its kinase domain, and subsequently phosphorylates eukaryotic initiation factor 2 alpha (eIF2 alpha). This results in attenuation of protein translation, preventing synthesis of necessary viral proteins. In certain DNA viruses, PKR function can be evaded by transcription of highly structured virus-encoded dsRNA inhibitors that bind to and inactivate PKR. We probe here the mechanism of PKR inhibition by two viral inhibitor RNAs, EBER1 (from Epstein-Barr) and VAT (from human adenovirus). Native gel shift mobility assays and isothermal titration calorimetry experiments confirmed that the RNA-binding domains of PKR are sufficient and necessary for the interaction with dsRNA inhibitors. Both EBER1 and VAT are effective inhibitors of PKR activation by preventing trans-autophosphorylation between two PKR molecules. The RNA inhibitors prevent self-association of PKR molecules, providing a mechanistic basis for kinase inhibition. A variety of approaches indicated that dsRNA inhibitors remain associated with PKR under activating conditions as opposed to activator dsRNA molecules that dissociate due to reduced affinity for the phosphorylated form of PKR. Finally, we show using a HeLa cell extract system that inhibitors of PKR result in translational recovery by the protein synthesis machinery. These data indicate that inhibitory dsRNAs bind preferentially to the latent, dephosphorylated form of PKR and prevent dimerization that is required for trans-autophosphorylation. (c) 2007 Elsevier Ltd. All rights reserved.
机译：宿主对病毒RNA基因组和复制产物的反应代表了对抗病毒入侵的有效策略。 PKR是一种Ser / Thr蛋白激酶，它与双链（ds）RNA结合，使其激酶结构域自磷酸化，然后使真核生物起始因子2α（eIF2 alpha）磷酸化。这导致蛋白质翻译的减弱，阻止了必需病毒蛋白质的合成。在某些DNA病毒中，可通过结合并灭活PKR的高度结构化的病毒编码dsRNA抑制剂的转录来逃避PKR功能。我们在这里探讨两种病毒抑制剂RNA，EBER1（来自爱泼斯坦-巴尔）和VAT（来自人腺病毒）对PKR的抑制作用。天然凝胶迁移迁移率测定法和等温滴定量热法实验证实，PKR的RNA结合域对于与dsRNA抑制剂的相互作用是足够的和必要的。通过防止两个PKR分子之间的反式自磷酸化作用，EBER1和VAT都是PKR激活的有效抑制剂。 RNA抑制剂可防止PKR分子的自缔合，从而为激酶抑制提供了机理基础。多种方法表明，dsRNA抑制剂在激活条件下仍与PKR相关，而不是由于对PKR磷酸化形式的亲和力降低而解离的激活剂dsRNA分子。最后，我们展示了使用HeLa细胞提取系统，PKR抑制剂可通过蛋白质合成机制导致翻译恢复。这些数据表明抑制性dsRNAs优先结合潜在的PKR的去磷酸化形式，并阻止反式自磷酸化所需的二聚化。 （c）2007 Elsevier Ltd.保留所有权利。

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