Preferential translation of host cell factors by hantavirus nucleocapsid protein

摘要：汉坦病毒是布尼亚病毒科的成员，包膜呈阴性。 链RNA病毒和A类病原体通过 受感染啮齿动物宿主的雾化排泄物。汉坦病毒已经进化出一种独特的 优先翻译他们的mRNAs的翻译机制。这项优惠 翻译是由汉坦病毒核衣壳蛋白(N-蛋白)进行的，它 与mRNA5‘帽和核糖体蛋白S19(RPS19)特异性结合，RPS19是一种结构性的 40S核糖体亚基的组成部分。此外，一种三聚体N-蛋白质分子 特异性地与高度保守的三联体重复序列(UAGUAGUAG)结合 病毒mRNA5‘非编码区。我们的结果表明N蛋白相关的核糖体是 选择性负载病毒5‘端非编码区以促进病毒转录本的翻译 宿主细胞胞质，其中细胞转录竞争相同的翻译 机械设备。有趣的是，我们的初步数据显示，N-蛋白质介导的翻译 策略也支持某些宿主细胞因子由未知的 机制。利用多方面的实验途径，我们将确定其机制 通过N蛋白介导的翻译选择性地翻译某些宿主细胞的mRNAs 策略。我们将确定宿主细胞因子的优先翻译是否起到了 在病毒复制中的作用。作为抗病毒反应，宿主细胞暂时关闭宿主 翻译机器为病毒蛋白质的合成制造障碍。这 抗病毒反应是由蛋白激酶R(PKR)的激活触发的，PKR 使其下游靶基因eif2α磷酸化，导致翻译关停。我们的 初步结果表明，N-蛋白抑制病毒感染细胞中PKR的激活 确保在感染过程中持续合成病毒蛋白质。我们将测试 N蛋白需要内源性宿主细胞因子辅助的假说 抑制PKR抗病毒反应。这些研究将揭示治疗的新靶点。 汉坦病毒病的干预。

Abstract: Hantaviruses, members of the Bunyaviridae family are enveloped negative strand RNA viruses and category A pathogens that are transmitted to humans through aerosolized excreta of infected rodent hosts. Hantaviruses have evolved a unique translation mechanism for the preferential translation of their mRNAs. This preferential translation is carried out by hantavirus nucleocapsid protein (N-protein) which specifically binds to the mRNA 5' cap and ribosomal protein S19 (RPS19), a structural component of the 40S ribosomal subunit. In addition, a trimeric N-protein molecule specifically binds to a highly conserved triplet repeat sequence (UAGUAGUAG) of the viral mRNA 5' UTR. Our results suggest that N-protein associated ribosomes are selectively loaded on viral mRNA 5' UTR to boost the translation of viral transcripts in the host cell cytoplasm where cellular transcripts are competing for the same translation machinery. Interestingly, our preliminary data shows that N-protein mediated translation strategy also favors the translation of certain host cell factors by an unknown mechanism. Using multifaceted experimental avenues we will determine the mechanism for the selective translation of certain host cell mRNAs by N-protein mediated translation strategy. We will determine whether preferential translation of host cell factors plays a role in virus replication. As antiviral response, host cells transiently shutdown the host translation machinery to create roadblocks for the synthesis of viral proteins. This antiviral response is triggered by the activation of protein kinase R (PKR), which phosphorylates its downstream target eIF2α, causing translational shutdown. Our preliminary results show that N-protein inhibits PKR activation in virus-infected cells to ensure continuous synthesis of viral proteins during the course of infection. We will test the hypothesis that N-protein requires the assistance from endogenous host cell factors to inhibit PKR antiviral response. These studies will reveal new targets for therapeutic intervention of hantavirus disease.