αvβ6- and αvβ8-integrins serve as interchangeable receptors for HSV gH/gL to promote endocytosis and activation of membrane fusion.
αvβ6- and αvβ8-integrins serve as interchangeable receptors for HSV gH/gL to promote endocytosis and activation of membrane fusion.
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DOI：
10.1371/journal.ppat.1003806
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Campadelli-Fiume G
中科院分区：
文献类型：
--
作者：
Gianni T;Salvioli S;Chesnokova LS;Hutt-Fletcher LM;Campadelli-Fiume G
单纯疱疹病毒（HSV）-和一般的疱疹病毒-编码多部分进入/融合装置。在HSV中，它由HSV特异性糖蛋白D（gD）和另外三种糖蛋白gH/gL和gB组成，所述三种糖蛋白在疱疹病毒科家族中是保守的并且负责融合的执行。根据目前的模型，在受体结合后，gD以级联方式将激活传播到gH/gL和gB。关于如何控制激活级联以及如何使其与病毒粒子内吞同步以避免过早激活和糖蛋白耗尽的问题仍然存在。我们考虑了这种控制可能是由未知的受体进行的可能性。事实上，已经描述了HSV gB的受体，但没有描述gH/gL的受体。在疱疹病毒科的其他成员中，例如EB病毒，整联蛋白受体结合gH/gL并触发糖蛋白的构象变化。我们报道了αvβ6-和αvβ8-整合素作为HSV进入角质形成细胞和其他上皮细胞和神经元细胞实验模型的受体。证据依赖于功能丧失实验，其中整合素被抗体阻断或沉默，以及功能获得实验，其中αvβ6-整合素在整合素阴性细胞中表达。αvβ6-和αvβ8-整联蛋白独立发挥作用，因此可以互换。两者均以高亲和力结合gH/gL。这种相互作用深刻地影响了HSV进入的途径，并将病毒导向酸性内体。在αvβ8而非αvβ6-整联蛋白的情况下，入口位于脂质微区，需要发动蛋白2。因此，αvβ6-或αvβ8-整联蛋白在HSV感染中的主要作用似乎是作为gH/gL受体起作用并促进病毒内吞作用。我们建议，将gH/gL激活下的整合素触发点，使HSV同步病毒粒子内吞与级联的糖蛋白激活，最终在执行融合。为了感染宿主并引起疾病，病毒必须进入宿主细胞。人类病原体单纯疱疹病毒（HSV）-和一般的疱疹病毒-配备有复杂的多部分进入装置，由四种糖蛋白- gD、gH/gL、gB组成。这些糖蛋白必须以及时、协调的方式被激活。根据目前的模型，激活通量从受体结合的gD到gH/gL和gB。还必须防止糖蛋白的过早激活和因此的耗尽。我们在gH/gL水平上报告一个检查点。具体而言，αvβ6-和αvβ8-整联蛋白作为HSV进入角质形成细胞和其他上皮细胞和神经元细胞的受体。两者均以高亲和力结合gH/gL。这种相互作用深刻地影响HSV进入的途径，促进HSV内吞进入酸性内体。对于αvβ8-整联蛋白，进入的门户是在脂质微区，需要发动蛋白2。我们提出，通过将gH/gL的激活置于整合素触发点的控制下，HSV可以使病毒体内吞与最终在病毒体包膜和细胞膜之间的融合的执行中达到高潮的激活级联同步。
Herpes simplex virus (HSV) - and herpesviruses in general - encode for a multipartite entry/fusion apparatus. In HSV it consists of the HSV-specific glycoprotein D (gD), and three additional glycoproteins, gH/gL and gB, conserved across the Herpesviridae family and responsible for the execution of fusion. According to the current model, upon receptor binding, gD propagates the activation to gH/gL and to gB in a cascade fashion. Questions remain about how the cascade of activation is controlled and how it is synchronized with virion endocytosis, to avoid premature activation and exhaustion of the glycoproteins. We considered the possibility that such control might be carried out by as yet unknown receptors. Indeed, receptors for HSV gB, but not for gH/gL, have been described. In other members of the Herpesviridae family, such as Epstein-Barr virus, integrin receptors bind gH/gL and trigger conformational changes in the glycoproteins. We report that αvβ6- and αvβ8-integrins serve as receptors for HSV entry into experimental models of keratinocytes and other epithelial and neuronal cells. Evidence rests on loss of function experiments, in which integrins were blocked by antibodies or silenced, and gain of function experiments in which αvβ6-integrin was expressed in integrin-negative cells. αvβ6- and αvβ8-integrins acted independently and are thus interchangeable. Both bind gH/gL with high affinity. The interaction profoundly affects the route of HSV entry and directs the virus to acidic endosomes. In the case of αvβ8, but not αvβ6-integrin, the portal of entry is located at lipid microdomains and requires dynamin 2. Thus, a major role of αvβ6- or αvβ8-integrin in HSV infection appears to be to function as gH/gL receptors and to promote virus endocytosis. We propose that placing the gH/gL activation under the integrin trigger point enables HSV to synchronize virion endocytosis with the cascade of glycoprotein activation that culminates in execution of fusion. In order to infect their hosts and cause disease, viruses must enter their host cells. The human pathogen herpes simplex virus (HSV) - and herpesviruses in general - are equipped with a complex, multipartite entry apparatus, made of four glycoproteins – gD, gH/gL, gB. These glycoproteins must be activated in a timely, coordinated manner. According to the current model, the flux of activation goes from receptor-bound gD, to gH/gL and gB. The premature activation, and hence exhaustion of the glycoproteins must also be prevented. We report on a checkpoint at the gH/gL level. Specifically, αvβ6- and αvβ8-integrins serve as receptors for HSV entry into keratinocytes and other epithelial and neuronal cells. Both bind gH/gL with high affinity. The interaction profoundly affects the pathway of HSV entry, promoting HSV endocytosis into acidic endosomes. For αvβ8-integrin, the portal of entry is at lipid microdomains and requires dynamin 2. We propose that, by placing the activation of gH/gL under control of an integrin trigger point, HSV can synchronize virion endocytosis with the cascade of activation that culminates in the execution of fusion between the virion envelope and cellular membranes.
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