Regulation of herpes simplex virus gB-induced cell-cell fusion by mutant forms of gH/gL in the absence of gD and cellular receptors.
Regulation of herpes simplex virus gB-induced cell-cell fusion by mutant forms of gH/gL in the absence of gD and cellular receptors.
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DOI：
10.1128/mbio.00046-13
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发表时间：
2013-02-26
期刊：
影响因子：
6.4
通讯作者：
Cohen GH
中科院分区：
文献类型：
--
作者：
Atanasiu D;Cairns TM;Whitbeck JC;Saw WT;Rao S;Eisenberg RJ;Cohen GH
疱疹病毒的进入需要gB和Gh/g1的病毒糖蛋白三联体在病毒粒子被膜和细胞膜之间进行融合，以便将核衣壳释放到靶细胞中。单纯疱疹病毒(HSV)也需要糖蛋白GD通过结合细胞受体如Nextin 1或疱疹病毒进入介体(HSEM)来启动融合级联反应。虽然gB的结构是III类融合蛋白，但Gh/gl没有类似于其他病毒融合蛋白的特征。相反，建议Gh/gl作为GB的调节器。用Gh N末端缺失28个残基的功能蛋白(GhΔ48/gl)获得了Gh/g1的晶体结构。无法解释的是，具有病毒中和活性的单抗(MAb)映射到这些残基上。为了协调这两个不同的观察结果，我们研究了GhΔ48/gl调节融合的能力。在这里，我们证明了在没有gD和/或受体的情况下，该蛋白可以诱导低水平的(结构性)融合。然而，当gD和受体存在时，该突变体的功能与野生型(Wt)Gh/gl的融合一样。我们认为GhΔ48/g1在导致完全调节激活的途径上具有中间结构。我们认为，融合途径中的关键步骤是受体结合的Gd将Gh/gl转变为激活状态，这种激活的Gh/gl类似于GhΔ48/gl。单纯疱疹病毒(HSV)导致许多人类疾病，从轻微的唇疱疹到致命的新生儿疱疹。作为一种包膜病毒，单纯疱疹病毒必须将其膜与宿主膜融合才能进行复制。病毒在这一过程中使用四种糖蛋白，Gd、Gb和Gh/gl，以及两种细胞受体之一，疱疹病毒进入介体(Hvem)和Nectin 1。虽然病毒可以通过直接在质膜上融合或通过内吞进入细胞，但涉及相同的四种糖蛋白。这些蛋白质中的任何一种都不存在，就会取消进入过程。在这里，我们证明了Gh/gl的一个突变形式，GhΔ48/gl，可以在没有Gd和Gd受体的情况下诱导表达Gb的细胞融合。我们的研究支持Gb是HSV FusoGen，其活性受Gh/Gl调节的观点。
Herpesvirus entry requires the viral glycoprotein triad of gB and gH/gL to carry out fusion between the virion envelope and a cellular membrane in order to release the nucleocapsid into the target cell. Herpes simplex virus (HSV) also requires glycoprotein gD to initiate the fusion cascade by binding a cell receptor such as nectin 1 or herpesvirus entry mediator (HVEM). While the structure of gB is that of a class III fusion protein, gH/gL has no features that resemble other viral fusion proteins. Instead, it is suggested that gH/gL acts as a regulator of gB. The crystal structure of HSV-2 gH/gL was obtained with a functional protein that had a deletion of 28 residues at the gH N terminus (gHΔ48/gL). Unexplainably, monoclonal antibodies (MAbs) with virus-neutralizing activity map to these residues. To reconcile these two disparate observations, we studied the ability of gHΔ48/gL to regulate fusion. Here, we show that the protein induces low (constitutive) levels of fusion by gB in the absence of gD and/or receptor. However, when gD and receptor are present, this mutant functions as well as does wild-type (wt) gH/gL for fusion. We propose that gHΔ48/gL has an intermediate structure on the pathway leading to full regulatory activation. We suggest that a key step in the pathway of fusion is the conversion of gH/gL to an activated state by receptor-bound gD; this activated gH/gL resembles gHΔ48/gL. Herpes simplex viruses (HSVs) cause many human diseases, from mild cold sores to lethal neonatal herpes. As an enveloped virus, HSV must fuse its membrane with a host membrane in order for replication to take place. The virus uses four glycoproteins for this process, gD, gB, and gH/gL, and either of two cell receptors, herpesvirus entry mediator (HVEM) and nectin 1. Although the virus can enter the cell by direct fusion at the plasma membrane or via endocytosis, the same four glycoproteins are involved. The absence of any of these proteins abolishes the entry process. Here, we show that a mutant form of gH/gL, gHΔ48/gL, can induce fusion of gB-expressing cells in the absence of gD and a gD receptor. Our study supports the concept that gB is the HSV fusogen and its activity is regulated by gH/gL.