Cascade of Events Governing Cell-Cell Fusion Induced by Herpes Simplex Virus Glycoproteins gD, gH/gL, and gB
Cascade of Events Governing Cell-Cell Fusion Induced by Herpes Simplex Virus Glycoproteins gD, gH/gL, and gB
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DOI：
10.1128/jvi.01700-10
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发表时间：
2010-12-01
影响因子：
5.4
通讯作者：
Eisenberg, Roselyn J.
中科院分区：
文献类型：
--
作者：
Atanasiu, Doina;Saw, Wan Ting;Eisenberg, Roselyn J.
疱疹病毒最少需要包膜蛋白gB和gH/gL来进行病毒侵入和细胞-细胞融合；单纯疱疹病毒（HSV）还需要受体结合蛋白gD。虽然gB是III类融合蛋白，但gH/gL在结构水平上与任何文献记载的病毒融合蛋白都不相似。基于这些数据，我们提出gH/gL不是作为gB的融合原，而是调节gB的融合活性。在这里，我们提供数据来支持这一假设。首先，表达gH/gL的受体阳性B78H1- c10细胞与表达gB和gD的受体阴性B78H1细胞融合（反式融合）。其次，当预先暴露于可溶性gD的表达gH/ gl的C10细胞随后与表达gb的B78细胞共培养时，发生融合。相比之下，先前将表达gb的C10细胞暴露于可溶性gD并没有促进随后与表达gH/ gl的B78细胞的融合。这些数据表明融合涉及受体结合gD对gH/gL的激活。最重要的是，可溶性gH/gL触发了表达gD和gB的C10细胞的低水平融合；当表达gb的C10细胞暴露于可溶性gH/gL和gD的组合中时，其水平要高得多。这些数据清楚地表明，在gD和gH/gL激活后，gB充当HSV的融合原。我们建议以下步骤导致融合：(i)受体结合后gD的构象改变，（ii）受体激活的gD改变gH/gL，以及（iii）与激活的gH/gL相互作用后gB的融合电位上调。第三步可能与其他疱疹病毒一样。
Herpesviruses minimally require the envelope proteins gB and gH/gL for virus entry and cell-cell fusion; herpes simplex virus (HSV) additionally requires the receptor-binding protein gD. Although gB is a class III fusion protein, gH/gL does not resemble any documented viral fusion protein at a structural level. Based on those data, we proposed that gH/gL does not function as a cofusogen with gB but instead regulates the fusogenic activity of gB. Here, we present data to support that hypothesis. First, receptor-positive B78H1-C10 cells expressing gH/gL fused with receptor-negative B78H1 cells expressing gB and gD (fusion in trans). Second, fusion occurred when gH/gL-expressing C10 cells preexposed to soluble gD were subsequently cocultured with gB-expressing B78 cells. In contrast, prior exposure of gB-expressing C10 cells to soluble gD did not promote subsequent fusion with gH/gL-expressing B78 cells. These data suggest that fusion involves activation of gH/gL by receptor-bound gD. Most importantly, soluble gH/gL triggered a low level of fusion of C10 cells expressing gD and gB; a much higher level was achieved when gB-expressing C10 cells were exposed to a combination of soluble gH/gL and gD. These data clearly show that gB acts as the HSV fusogen following activation by gD and gH/gL. We suggest the following steps leading to fusion: (i) conformational changes to gD upon receptor binding, (ii) alteration of gH/gL by receptor-activated gD, and (iii) upregulation of the fusogenic potential of gB following its interaction with activated gH/gL. The third step may be common to other herpesviruses.