Andes virus nucleocapsid protein interrupts protein kinase R dimerization to counteract host interference in viral protein synthesis.
Andes virus nucleocapsid protein interrupts protein kinase R dimerization to counteract host interference in viral protein synthesis.
复制标题
安第斯病毒核衣壳蛋白中断蛋白激酶 R 二聚化，以抵消宿主对病毒蛋白合成的干扰。
DOI：
10.1128/jvi.02347-14
复制
发表时间：
2015
影响因子：
5.4
通讯作者：
Mir,MohammadA
中科院分区：
文献类型：
--
作者：
Wang,Zekun;Mir,MohammadA
致病性汉坦病毒在病毒感染的早期阶段延迟I型干扰素应答。然而，在汉他病毒感染的后期阶段观察到的强干扰素应答和干扰素刺激基因的诱导未能对抗感染细胞中的病毒复制。蛋白激酶R（PKR）是一种经典的干扰素刺激的基因产物，可磷酸化真核生物的翻译起始因子eIF2α，导致翻译关闭，为病毒蛋白的合成制造障碍。PKR诱导的翻译关闭有助于宿主细胞建立抗病毒状态以中断病毒复制。然而，汉他病毒感染的细胞在病毒感染过程中不经历翻译关闭，并且不能建立抗病毒状态。在这项研究中，我们首次发现安第斯山脉病毒感染诱导PKR过表达。然而，过表达的PKR是没有活性的，由于一个显着的抑制自磷酸化。进一步的研究表明，安第斯山脉病毒核衣壳蛋白抑制PKR二聚化，这是PKR自磷酸化获得活性所需的关键步骤。本文报道的研究确立了汉坦病毒核衣壳蛋白作为一种新的PKR抑制剂。这些研究为汉他病毒对宿主干扰素反应的抗性提供了机制上的见解，并解决了汉他病毒感染细胞中观察到的翻译关闭缺乏的难题。汉他病毒复制对PKR的敏感性可能对汉他病毒施加了选择性进化压力，以逃避PKR抗病毒反应以生存。我们设想，逃避PKR抗病毒反应的NP可能有助于汉坦病毒在进化过程中存在，并在感染的宿主中生存，具有多方面的抗病毒防御。重要信息蛋白激酶R（PKR），一种多功能的抗病毒宿主因子，在病毒感染的细胞中激活后关闭翻译机器，为病毒蛋白的制造障碍。本文报道的研究表明，汉坦病毒核衣壳蛋白通过抑制PKR二聚化来抵消PKR的抗病毒反应，而PKR二聚化是其激活所必需的。我们报告发现了一种新的PKR抑制剂，其在汉他病毒感染的细胞中的表达防止PKR诱导的宿主翻译关闭，以确保有效的病毒复制所需的病毒蛋白质的连续合成。
Pathogenic hantaviruses delay the type I interferon response during early stages of viral infection. However, the robust interferon response and induction of interferon-stimulated genes observed during later stages of hantavirus infection fail to combat the virus replication in infected cells. Protein kinase R (PKR), a classical interferon-stimulated gene product, phosphorylates the eukaryotic translation initiation factor eIF2α and causes translational shutdown to create roadblocks for the synthesis of viral proteins. The PKR-induced translational shutdown helps host cells to establish an antiviral state to interrupt virus replication. However, hantavirus-infected cells do not undergo translational shutdown and fail to establish an antiviral state during the course of viral infection. In this study, we showed for the first time that Andes virus infection induced PKR overexpression. However, the overexpressed PKR was not active due to a significant inhibition of autophosphorylation. Further studies revealed that Andes virus nucleocapsid protein inhibited PKR dimerization, a critical step required for PKR autophosphorylation to attain activity. The studies reported here establish a hantavirus nucleocapsid protein as a new PKR inhibitor. These studies provide mechanistic insights into hantavirus resistance to the host interferon response and solve the puzzle of the lack of translational shutdown observed in hantavirus-infected cells. The sensitivity of hantavirus replication to PKR has likely imposed a selective evolutionary pressure on hantaviruses to evade the PKR antiviral response for survival. We envision that evasion of the PKR antiviral response by NP has likely helped hantaviruses to exist during evolution and to survive in infected hosts with a multifaceted antiviral defense.IMPORTANCEProtein kinase R (PKR), a versatile antiviral host factor, shuts down the translation machinery upon activation in virus-infected cells to create hurdles for the manufacture of viral proteins. The studies reported here reveal that the hantavirus nucleocapsid protein counteracts the PKR antiviral response by inhibiting PKR dimerization, which is required for its activation. We report the discovery of a new PKR inhibitor whose expression in hantavirus-infected cells prevents the PKR-induced host translational shutdown to ensure the continuous synthesis of viral proteins required for efficient virus replication.