Binding of HSV-1 Glycoprotein K (gK) to Signal Peptide Peptidase (SPP) Is Required for Virus Infectivity

Glycoprotein K (gK) is a virion envelope protein of herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), which plays important roles in virion entry, morphogenesis and egress. Two-hybrid and pull-down assays were utilized to demonstrate that gK and no other HSV-1 genes specifically binds to signal peptide peptidase (SPP), also known as minor histocompatibility antigen H13. SPP dominant negative mutants, shRNA against SPP significantly reduced HSV-1 replication in vitro. SPP also affected lysosomes and ER responses to HSV-1 infection. Thus, in this study we have shown for the first time that gK, despite its role in fusion and egress, is also involved in binding the cytoplasmic protein SPP. These results also suggest that SPP plays an important role in viral replication and possibly virus pathogenesis. This makes SPP unique in that its function appears to be required by the virus as no other protein can compensate its loss in terms of viral replication.糖蛋白K（Glycoprotein K，gK）是1型单纯疱疹病毒（Herpes Simplex Virus 1，HSV-1）与2型单纯疱疹病毒（Herpes Simplex Virus 2，HSV-2）的病毒体囊膜蛋白，在病毒侵入、形态发生及病毒释放过程中发挥关键作用。本研究采用酵母双杂交与亲和下拉实验证实，仅gK而非其他HSV-1编码基因可特异性结合信号肽肽酶（Signal Peptide Peptidase，SPP），该蛋白亦被称为次要组织相容性抗原H13。SPP显性负突变体及靶向SPP的短发夹RNA（short hairpin RNA，shRNA）可显著降低体外培养体系中HSV-1的复制水平。SPP同时可调控溶酶体与内质网（Endoplasmic Reticulum，ER）对HSV-1感染的应答反应。本研究首次证实：尽管gK已被证实参与病毒融合与释放过程，其同时可结合胞质蛋白SPP。上述结果提示，SPP在病毒复制乃至病毒致病机制中均发挥重要作用。尤为值得注意的是，SPP的功能具有不可替代性——目前尚未发现其他蛋白可弥补SPP缺失对病毒复制造成的缺陷，这使得SPP在病毒-宿主互作体系中具有独特性。