Third Helical Domain of the Nipah Virus Fusion Glycoprotein Modulates both Early and Late Steps in the Membrane Fusion Cascade.
Third Helical Domain of the Nipah Virus Fusion Glycoprotein Modulates both Early and Late Steps in the Membrane Fusion Cascade.
复制标题
尼帕病毒融合糖蛋白的第三螺旋结构域调节膜融合级联的早期和晚期步骤。
DOI：
10.1128/jvi.00644-20
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发表时间：
2020
影响因子：
5.4
通讯作者：
Aguilar,HectorC
中科院分区：
文献类型：
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作者：
Zamora,JLizbethReyes;Ortega,Victoria;Johnston,GunnerP;Li,Jenny;André,NicoleM;Monreal,IAbrrey;Contreras,ErikM;Whittaker,GaryR;Aguilar,HectorC
医学上重要的副粘病毒，如麻疹、腮腺炎、副流感病毒、尼帕病毒和亨德拉病毒，通过引导病毒和细胞质膜的融合来感染宿主细胞。感染后，副粘病毒引起第二种类型的膜融合，细胞-细胞融合（合胞体形成），这与致病性有关。宿主细胞受体结合引起附着糖蛋白（HN、H或G）的构象变化，从而触发介导膜融合的融合（F）糖蛋白的构象级联。F是一种I类融合蛋白，含有原型七肽重复区1（HR 1）和2（HR 2）。已经确定HR 1和HR 2的结合是融合病毒和细胞膜的关键。在这项研究中，我们发现了一个新的融合调节作用的第三个结构保守的螺旋区（HR 3）在F。基于其在F结构中的位置，以及其融合前和融合后构象之间的结构差异，我们假设HR 3调节F构象级联的触发（仍然需要G）。我们使用致命的尼帕病毒（NiV）作为一个重要的副粘病毒模型进行丙氨酸扫描诱变和一系列多学科的结构/功能分析，解剖膜融合级联的各种状态。值得注意的是，我们发现HR 3内的特定残基不仅调节早期F-触发，而且调节膜融合级联中的晚期广泛融合孔扩张步骤。我们的研究结果的特点，这些新的融合调节作用的F HR 3，提高我们对膜融合过程的理解NiV和可能为relatedHenipavirusgenus和possiblyParamyxoviridae familymembers. IMPORTANCETheParamyxoviridae family. Importance包括重要的人类和动物病原体，如麻疹，腮腺炎，副流感病毒和致命的henipaviruses尼帕（NiV）和亨德拉（HeV）病毒。副粘病毒感染呼吸道和中枢神经系统（CNS），并且可以是高度传染性的。大多数副粘病毒的宿主范围有限。然而，生物安全等级4的NiV和HeV具有高致病性，并且具有广泛的哺乳动物宿主范围。尼帕病毒感染导致人类急性呼吸道综合征和严重脑炎，导致40%至100%的死亡率。由于缺乏针对NiV和其他重要副粘病毒的许可疫苗或治疗方法，因此需要了解病毒进入机制。在这项研究中，我们发现了一个新的作用的第三螺旋区（HR 3）的NiV融合糖蛋白的膜融合过程中，导致病毒进入。这一发现使HR 3成为NiV抗病毒策略的新候选靶标，并可能用于相关病毒。
Medically important paramyxoviruses, such as measles, mumps, parainfluenza, Nipah, and Hendra viruses, infect host cells by directing fusion of the viral and cellular plasma membranes. Upon infection, paramyxoviruses cause a second type of membrane fusion, cell-cell fusion (syncytium formation), which is linked to pathogenicity. Host cell receptor binding causes conformational changes in the attachment glycoprotein (HN, H, or G) that trigger a conformational cascade in the fusion (F) glycoprotein that mediates membrane fusion. F, a class I fusion protein, contains the archetypal heptad repeat regions 1 (HR1) and 2 (HR2). It is well established that binding of HR1 and HR2 is key to fusing viral and cellular membranes. In this study, we uncovered a novel fusion-modulatory role of a third structurally conserved helical region (HR3) in F. Based on its location within the F structure, and structural differences between its prefusion and postfusion conformations, we hypothesized that the HR3 modulates triggering of the F conformational cascade (still requiring G). We used the deadly Nipah virus (NiV) as an important paramyxoviral model to perform alanine scan mutagenesis and a series of multidisciplinary structural/functional analyses that dissect the various states of the membrane fusion cascade. Remarkably, we found that specific residues within the HR3 modulate not only early F-triggering but also late extensive fusion pore expansion steps in the membrane fusion cascade. Our results characterize these novel fusion-modulatory roles of the F HR3, improving our understanding of the membrane fusion process for NiV and likely for the relatedHenipavirusgenus and possiblyParamyxoviridaefamily members.IMPORTANCETheParamyxoviridaefamily includes important human and animal pathogens, such as measles, mumps, and parainfluenza viruses and the deadly henipaviruses Nipah (NiV) and Hendra (HeV) viruses. Paramyxoviruses infect the respiratory tract and the central nervous system (CNS) and can be highly infectious. Most paramyxoviruses have a limited host range. However, the biosafety level 4 NiV and HeV are highly pathogenic and have a wide mammalian host range. Nipah viral infections result in acute respiratory syndrome and severe encephalitis in humans, leading to 40 to 100% mortality rates. The lack of licensed vaccines or therapeutic approaches against NiV and other important paramyxoviruses underscores the need to understand viral entry mechanisms. In this study, we uncovered a novel role of a third helical region (HR3) of the NiV fusion glycoprotein in the membrane fusion process that leads to viral entry. This discovery sets HR3 as a new candidate target for antiviral strategies for NiV and likely for related viruses.