Assembly and budding of influenza virus.
Assembly and budding of influenza virus.
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DOI：
10.1016/j.virusres.2004.08.012
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发表时间：
2004-12
期刊：
影响因子：
5
通讯作者：
Barman S
中科院分区：
文献类型：
--
作者：
Nayak DP;Hui EK;Barman S
流感病毒是称为流感的急性发热性呼吸道疾病（通常称为“流感”）的病原体，属于正粘病毒科。这些病毒具有分段的负链RNA基因组（vRNA），并且被包膜，通常为球形，并且从质膜（更具体地，极化上皮细胞的顶端质膜）出芽。因此，在受感染的细胞内没有发现完整的病毒颗粒。病毒颗粒由三种主要亚病毒组分组成，即病毒包膜、基质蛋白（M1）和核心（病毒核糖核衣壳[vRNP]）。围绕vRNP的病毒包膜由脂质双层组成，脂质双层含有由病毒糖蛋白（HA、NA和M2）组成的刺突（在外侧）和M1（在内侧）。来自宿主质膜的病毒脂质选择性富集胆固醇和鞘糖脂。M1形成病毒包膜和核心之间的桥梁。病毒核心由含有vRNA（负链）和NP的螺旋vRNP沿着少量NEP和聚合酶复合物（PA、PB1和PB2）组成。为了发生病毒形态发生，所有三种病毒组分，即病毒包膜（含有脂质和跨膜蛋白）、M1和vRNP必须被带到组装位点，即极化上皮细胞中的顶端质膜。最后，必须在组装位点形成芽，并且随着芽的闭合释放病毒颗粒。跨膜病毒蛋白通过胞吐途径转运到质膜上的组装位点。HA和NA都具有顶端分选信号，并使用脂筏进行细胞表面转运和顶端分选。这些脂筏富含胆固醇、鞘糖脂，并且在低温下对中性洗涤剂提取具有相对抗性。M1在游离的胞质多聚核糖体上合成。vRNP在宿主细胞核内产生，并在M1和NEP的帮助下通过核孔输出到细胞质中。M1和vRNP如何被定向到质膜上的组装位点仍不清楚。可能的可能性是，它们使用了病毒糖蛋白或细胞骨架元件的背驮机制。或者，它们可能拥有顶端决定簇或扩散到组装位点，或这些途径的组合。M1与M1、M1与vRNP以及M1与HA和NA的相互作用促进病毒组分的浓缩并将宿主蛋白从出芽位点排除。M1与糖蛋白的胞质尾区（CT）和跨膜结构域（TMD）相互作用，从而起到病毒包膜和vRNP之间的桥梁作用。脂筏作为浓缩病毒糖蛋白的微结构域，并可作为病毒出芽的平台。病毒芽的形成需要在芽生部位的膜弯曲。包括病毒组分的浓度和相互作用、脂筏的脂双层的粘度增加和不对称性以及病毒和宿主组分的拉力和推力在内的因素的组合可能导致质膜在组装位点处向外弯曲，从而导致芽形成。最后，病毒释放需要芽由于并置膜的融合而完成，导致芽闭合，病毒颗粒从宿主质膜分离并释放到细胞外环境中。在病毒组分中，M1含有L结构域基序，在出芽中起关键作用。芽的完成不仅需要病毒成分，还需要宿主成分。然而，宿主成分如何促进芽的完成仍不清楚。除了芽完成，流感病毒需要NA从细胞表面的唾液酸残基释放病毒颗粒，并在细胞间传播。阐明参与病毒形态发生和出芽的病毒和宿主因素可能导致开发干扰病毒形态发生步骤和疾病进展的药物。
Influenza viruses are causative agents of an acute febrile respiratory disease called influenza (commonly known as “flu”) and belong to the Orthomyxoviridae family. These viruses possess segmented, negative stranded RNA genomes (vRNA) and are enveloped, usually spherical and bud from the plasma membrane (more specifically, the apical plasma membrane of polarized epithelial cells). Complete virus particles, therefore, are not found inside infected cells. Virus particles consist of three major subviral components, namely the viral envelope, matrix protein (M1), and core (viral ribonucleocapsid [vRNP]). The viral envelope surrounding the vRNP consists of a lipid bilayer containing spikes composed of viral glycoproteins (HA, NA, and M2) on the outer side and M1 on the inner side. Viral lipids, derived from the host plasma membrane, are selectively enriched in cholesterol and glycosphingolipids. M1 forms the bridge between the viral envelope and the core. The viral core consists of helical vRNP containing vRNA (minus strand) and NP along with minor amounts of NEP and polymerase complex (PA, PB1, and PB2). For viral morphogenesis to occur, all three viral components, namely the viral envelope (containing lipids and transmembrane proteins), M1, and the vRNP must be brought to the assembly site, i.e. the apical plasma membrane in polarized epithelial cells. Finally, buds must be formed at the assembly site and virus particles released with the closure of buds. Transmembrane viral proteins are transported to the assembly site on the plasma membrane via the exocytic pathway. Both HA and NA possess apical sorting signals and use lipid rafts for cell surface transport and apical sorting. These lipid rafts are enriched in cholesterol, glycosphingolipids and are relatively resistant to neutral detergent extraction at low temperature. M1 is synthesized on free cytosolic polyribosomes. vRNPs are made inside the host nucleus and are exported into the cytoplasm through the nuclear pore with the help of M1 and NEP. How M1 and vRNPs are directed to the assembly site on the plasma membrane remains unclear. The likely possibilities are that they use a piggy-back mechanism on viral glycoproteins or cytoskeletal elements. Alternatively, they may possess apical determinants or diffuse to the assembly site, or a combination of these pathways. Interactions of M1 with M1, M1 with vRNP, and M1 with HA and NA facilitate concentration of viral components and exclusion of host proteins from the budding site. M1 interacts with the cytoplasmic tail (CT) and transmembrane domain (TMD) of glycoproteins, and thereby functions as a bridge between the viral envelope and vRNP. Lipid rafts function as microdomains for concentrating viral glycoproteins and may serve as a platform for virus budding. Virus bud formation requires membrane bending at the budding site. A combination of factors including concentration of and interaction among viral components, increased viscosity and asymmetry of the lipid bilayer of the lipid raft as well as pulling and pushing forces of viral and host components are likely to cause outward curvature of the plasma membrane at the assembly site leading to bud formation. Eventually, virus release requires completion of the bud due to fusion of the apposing membranes, leading to the closure of the bud, separation of the virus particle from the host plasma membrane and release of the virus particle into the extracellular environment. Among the viral components, M1 contains an L domain motif and plays a critical role in budding. Bud completion requires not only viral components but also host components. However, how host components facilitate bud completion remains unclear. In addition to bud completion, influenza virus requires NA to release virus particles from sialic acid residues on the cell surface and spread from cell to cell. Elucidation of both viral and host factors involved in viral morphogenesis and budding may lead to the development of drugs interfering with the steps of viral morphogenesis and in disease progression.
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