Liu Qian, Bradel-Tretheway Birgit, Monreal Abrrey I, Saludes Jonel P, Lu Xiaonan, Nicola Anthony V, Aguilar Hector C
Paul G. Allen School for Global Animal Health, Washington State University, Pullman, Washington, USA.
Department of Chemistry, Washington State University, Pullman, Washington, USA.
J Virol. 2015 Feb;89(3):1838-50. doi: 10.1128/JVI.02277-14. Epub 2014 Nov 26.
Membrane fusion is essential for paramyxovirus entry into target cells and for the cell-cell fusion (syncytia) that results from many paramyxoviral infections. The concerted efforts of two membrane-integral viral proteins, the attachment (HN, H, or G) and fusion (F) glycoproteins, mediate membrane fusion. The emergent Nipah virus (NiV) is a highly pathogenic and deadly zoonotic paramyxovirus. We recently reported that upon cell receptor ephrinB2 or ephrinB3 binding, at least two conformational changes occur in the NiV-G head, followed by one in the NiV-G stalk, that subsequently result in F triggering and F execution of membrane fusion. However, the domains and residues in NiV-G that trigger F and the specific events that link receptor binding to F triggering are unknown. In the present study, we identified a NiV-G stalk C-terminal region (amino acids 159 to 163) that is important for multiple G functions, including G tetramerization, conformational integrity, G-F interactions, receptor-induced conformational changes in G, and F triggering. On the basis of these results, we propose that this NiV-G region serves as an important structural and functional linker between the NiV-G head and the rest of the stalk and is critical in propagating the F-triggering signal via specific conformational changes that open a concealed F-triggering domain(s) in the G stalk. These findings broaden our understanding of the mechanism(s) of receptor-induced paramyxovirus F triggering during viral entry and cell-cell fusion.
The emergent deadly viruses Nipah virus (NiV) and Hendra virus belong to the Henipavirus genus in the Paramyxoviridae family. NiV infections target endothelial cells and neurons and, in humans, result in 40 to 75% mortality rates. The broad tropism of the henipaviruses and the unavailability of therapeutics threaten the health of humans and livestock. Viral entry into host cells is the first step of henipavirus infections, which ultimately cause syncytium formation. After attaching to the host cell receptor, henipaviruses enter the target cell via direct viral-cell membrane fusion mediated by two membrane glycoproteins: the attachment protein (G) and the fusion protein (F). In this study, we identified and characterized a region in the NiV-G stalk C-terminal domain that links receptor binding to fusion triggering via several important glycoprotein functions. These findings advance our understanding of the membrane fusion-triggering mechanism(s) of the henipaviruses and the paramyxoviruses.
膜融合对于副粘病毒进入靶细胞以及许多副粘病毒感染所导致的细胞-细胞融合（合胞体形成）至关重要。两种膜整合病毒蛋白，即附着（HN、H或G）糖蛋白和融合（F）糖蛋白的协同作用介导膜融合。新出现的尼帕病毒（NiV）是一种高致病性致命人畜共患副粘病毒。我们最近报道，在细胞受体ephrinB2或ephrinB3结合后，NiV-G头部至少发生两种构象变化，随后NiV-G茎部发生一种构象变化，这随后导致F触发以及膜融合的F执行。然而，NiV-G中触发F的结构域和残基以及将受体结合与F触发联系起来的具体事件尚不清楚。在本研究中，我们鉴定出NiV-G茎部C末端区域（氨基酸159至163），其对于多种G功能很重要，包括G四聚化、构象完整性、G-F相互作用、受体诱导的G构象变化以及F触发。基于这些结果，我们提出该NiV-G区域作为NiV-G头部与茎部其余部分之间重要的结构和功能连接体，并且在通过特定构象变化传播F触发信号方面至关重要，这些构象变化会打开G茎部中一个隐藏的F触发结构域。这些发现拓宽了我们对病毒进入和细胞-细胞融合过程中受体诱导的副粘病毒F触发机制的理解。
新出现的致命病毒尼帕病毒（NiV）和亨德拉病毒属于副粘病毒科的亨尼帕病毒属。NiV感染靶向内皮细胞和神经元，在人类中导致40%至75%的死亡率。亨尼帕病毒广泛的嗜性以及缺乏治疗方法威胁着人类和牲畜的健康。病毒进入宿主细胞是亨尼帕病毒感染的第一步，最终导致合胞体形成。在附着于宿主细胞受体后，亨尼帕病毒通过两种膜糖蛋白介导的直接病毒-细胞膜融合进入靶细胞：附着蛋白（G）和融合蛋白（F）。在本研究中，我们鉴定并表征了NiV-G茎部C末端结构域中的一个区域，该区域通过几种重要的糖蛋白功能将受体结合与融合触发联系起来。这些发现推进了我们对亨尼帕病毒和副粘病毒膜融合触发机制的理解。
