The KGD Motif of Epstein-Barr Virus gH/gL Is Bifunctional, Orchestrating Infection of B Cells and Epithelial Cells
The KGD Motif of Epstein-Barr Virus gH/gL Is Bifunctional, Orchestrating Infection of B Cells and Epithelial Cells
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DOI：
10.1128/mbio.00290-11
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发表时间：
2012-01-01
期刊：
影响因子：
6.4
通讯作者：
Longnecker, Richard
中科院分区：
文献类型：
--
作者：
Chen, Jia;Rowe, Cynthia L.;Longnecker, Richard
EB病毒（Epstein-Barr virus，EBV）是疱疹病毒家族的成员，是常见人类感染和特定恶性肿瘤的病原体。EBV进入靶细胞，包括B细胞和上皮细胞，需要多种病毒编码的糖蛋白的相互作用。糖蛋白H和L（gH/gL）与糖蛋白B（gB）协作以介导病毒包膜与靶细胞膜的融合。融合需要gH/gL复合物和gB，而糖蛋白42（gp 42）作为向性开关，是B细胞感染所需的，并抑制上皮细胞感染。我们以前的研究确定了一个突出的KGD基序位于表面的gH/gL。在目前的研究中，我们发现，这个基序作为一个双功能域的表面上的gH/gL，指导EBV融合的B细胞和上皮细胞。KGD基序突变为AAA减少了与上皮细胞和B细胞的融合，并减少了gH/gL与上皮细胞和gp 42的结合。我们还证明gp 42的氨基酸62至66的缺失选择性地减少了与野生型gH/gL的结合，但不是KGD突变体，这表明gH/gL的KGD基序与gp 42的N-末端氨基酸62至66相互作用。重要意义上皮细胞和B细胞是Epstein-Barr病毒（EBV）感染人类宿主的主要靶细胞。EBV利用不同的糖蛋白复合物进入这些细胞类型。对于B细胞融合，EBV使用含有gp 42、gH/gL和gB的复合物，而上皮细胞融合仅需要gH/gL和gB。在目前的研究中，一个双功能结构域组成的一个突出的KGD基序的表面上的gH/gL结构被确定;该域影响与gp 42或上皮受体的相互作用，最终决定与细胞类型的病毒诱导的融合可以发生。这些研究将导致更好地了解EB病毒诱导的膜融合和疱疹病毒诱导的膜融合的机制。
Epstein-Barr virus (EBV), a member of the herpesvirus family, is the causative agent of common human infections and specific malignancies. EBV entry into target cells, including B cells and epithelial cells, requires the interaction of multiple virus-encoded glycoproteins. Glycoproteins H and L (gH/gL) cooperate with glycoprotein B (gB) to mediate fusion of the viral envelope with target cell membranes. Both the gH/gL complex and gB are required for fusion, whereas glycoprotein 42 (gp42) acts as a tropism switch and is required for B cell infection and inhibits epithelial cell infection. Our previous studies identified a prominent KGD motif located on the surface of gH/gL. In the current study, we found that this motif serves as a bifunctional domain on the surface of gH/gL that directs EBV fusion of B cells and epithelial cells. Mutation of the KGD motif to AAA decreased fusion with both epithelial and B cells and reduced the binding of gH/gL to epithelial cells and to gp42. We also demonstrate that deletion of amino acids 62 to 66 of gp42 selectively reduces binding to wild-type gH/gL, but not the KGD mutant, suggesting that the KGD motif of gH/gL interacts with the N-terminal amino acids 62 to 66 of gp42.IMPORTANCE Epithelial and B cells are the major targets of Epstein-Barr virus (EBV) infection in the human host. EBV utilizes different glycoprotein complexes to enter these cell types. For B cell fusion, EBV uses complexes containing gp42, gH/gL, and gB, whereas just gH/gL and gB are required for epithelial cell fusion. In the current study, a bifunctional domain consisting of a prominent KGD motif on the surface of the gH/gL structure was identified; this domain affects interactions with gp42 or epithelial receptors, ultimately dictating with which cell type virus-induced fusion can occur. These studies will lead to a better understanding of the mechanism of EBV-induced membrane fusion and herpesvirus-induced membrane fusion in general.