Structurally Conserved Domains between Flavivirus and Alphavirus Fusion Glycoproteins Contribute to Replication and Infectious-Virion Production.
Structurally Conserved Domains between Flavivirus and Alphavirus Fusion Glycoproteins Contribute to Replication and Infectious-Virion Production.
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黄病毒和甲病毒融合糖蛋白之间的结构保守域有助于复制和感染性病毒颗粒的产生。
DOI：
10.1128/jvi.01774-21
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发表时间：
2022
影响因子：
5.4
通讯作者：
Stapleford,KennethA
中科院分区：
文献类型：
--
作者：
Rangel,MargaritaV;Catanzaro,Nicholas;Thannickal,SaraA;Crotty,KellyA;Noval,MariaG;Johnson,KatherineEE;Ghedin,Elodie;Lazear,HelenM;Stapleford,KennethA
甲病毒和黄病毒具有II类融合糖蛋白，其对于病毒体组装和感染性是必需的。重要的是，结构域II的尖端在甲病毒和黄病毒融合蛋白之间是结构保守的，但病毒家族之间的这些结构相似性是否转化为功能相似性尚不清楚。利用寨卡病毒（ZIKV）的体内进化，我们鉴定了几种新出现的变体，包括结构域II的β-链c（V114 M）中的包膜糖蛋白变体。我们先前已经证明，位于甲病毒E1糖蛋白结构域II尖端的类似β链c和ij环对感染性很重要。这使我们假设黄病毒E β-链c也有助于黄病毒感染。我们产生了这种ZIKV糖蛋白变体，并发现虽然它对蚊子的感染几乎没有影响，但它减少了人类细胞和小鼠中的复制，并增加了病毒对氯化铵的敏感性，如甲病毒所见。鉴于这些结果并且鉴于我们的甲病毒ij环研究，我们将黄病毒ij环尖端的保守丙氨酸突变为缬氨酸以测试其对ZIKV感染性的影响。有趣的是，这种突变抑制了ZIKV和黄热病病毒的感染性病毒体产生，但不抑制西尼罗河病毒。总之，这些研究表明，甲病毒和黄病毒II类融合糖蛋白的共享结构域具有结构相似的残基，这些残基在功能上很重要，并有助于体内病毒感染。重要的是，虫媒病毒是一个重大的全球公共卫生威胁，但没有针对这些病毒的抗病毒药物。这个问题部分是由于我们缺乏知识的分子机制，在虫媒病毒的生命周期。特别是，病毒进入和组装是病毒生命周期中的重要过程，也是开发抗病毒疗法的目标步骤。因此，了解不同虫媒病毒进入和组装的共同基本机制是至关重要的。在这项研究中，我们表明，黄病毒和甲病毒的残基位于结构保守和类似的区域的II类融合蛋白有助于共同的机制，进入，传播和感染性病毒粒子的生产。这些研究突出了II类融合蛋白的功能，并为开发抗病毒药物提供了新的靶点。
Alphaviruses and flaviviruses have class II fusion glycoproteins that are essential for virion assembly and infectivity. Importantly, the tip of domain II is structurally conserved between the alphavirus and flavivirus fusion proteins, yet whether these structural similarities between virus families translate to functional similarities is unclear. Usingin vivoevolution of Zika virus (ZIKV), we identified several novel emerging variants, including an envelope glycoprotein variant in β-strand c (V114M) of domain II. We have previously shown that the analogous β-strand c and the ij loop, located in the tip of domain II of the alphavirus E1 glycoprotein, are important for infectivity. This led us to hypothesize that flavivirus E β-strand c also contributes to flavivirus infection. We generated this ZIKV glycoprotein variant and found that while it had little impact on infection in mosquitoes, it reduced replication in human cells and mice and increased virus sensitivity to ammonium chloride, as seen for alphaviruses. In light of these results and given our alphavirus ij loop studies, we mutated a conserved alanine at the tip of the flavivirus ij loop to valine to test its effect on ZIKV infectivity. Interestingly, this mutation inhibited infectious virion production of ZIKV and yellow fever virus, but not West Nile virus. Together, these studies show that shared domains of the alphavirus and flavivirus class II fusion glycoproteins harbor structurally analogous residues that are functionally important and contribute to virus infectionin vivo.IMPORTANCEArboviruses are a significant global public health threat, yet there are no antivirals targeting these viruses. This problem is in part due to our lack of knowledge of the molecular mechanisms involved in the arbovirus life cycle. In particular, virus entry and assembly are essential processes in the virus life cycle and steps that can be targeted for the development of antiviral therapies. Therefore, understanding common, fundamental mechanisms used by different arboviruses for entry and assembly is essential. In this study, we show that flavivirus and alphavirus residues located in structurally conserved and analogous regions of the class II fusion proteins contribute to common mechanisms of entry, dissemination, and infectious-virion production. These studies highlight how class II fusion proteins function and provide novel targets for development of antivirals.
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