Cellular interactome of HSV-1 pUL21

The herpes simplex virus (HSV)-1 protein pUL21 is essential for efficient virus replication and dissemination. While pUL21 has been shown to promote multiple steps of virus assembly and spread, the molecular basis of its function remained unclear. Here we identify that pUL21 is a virus-encoded adaptor of protein phosphatase 1 (PP1). pUL21 directs the dephosphorylation of cellular and virus proteins, including components of the viral nuclear egress complex, and we define a conserved non-canonical linear motif in pUL21 that is essential for PP1 recruitment. In vitro evolution experiments reveal that pUL21 directly antagonises the activity of the virus-encoded kinase pUS3, with growth and spread of pUL21 PP1-binding mutant viruses being restored when pUS3 activity is disrupted. This study shows that virus-directed phosphatase activity is essential for efficient herpesvirus assembly and spread, highlighting the fine balance between kinase and phosphatase activity required for optimal virus replication.

单纯疱疹病毒1型（herpes simplex virus 1，HSV-1）的pUL21蛋白对于病毒高效复制与播散至关重要。尽管已有研究证实pUL21可促进病毒组装与传播的多个环节，但其发挥功能的分子基础仍未阐明。本研究证实pUL21是一种病毒编码的蛋白磷酸酶1（protein phosphatase 1，PP1）适配蛋白。pUL21可介导细胞及病毒蛋白（包括病毒核出复合物（viral nuclear egress complex）的组分）的去磷酸化修饰；我们还鉴定出pUL21中一段保守的非经典线性基序，该基序对PP1的招募不可或缺。体外进化实验表明，pUL21可直接拮抗病毒编码的激酶pUS3的活性；当pUS3活性被阻断时，无法结合PP1的pUL21突变病毒的增殖与播散能力得以恢复。本研究表明，病毒介导的磷酸酶活性对于疱疹病毒的高效组装与传播必不可少，同时也凸显了实现最优病毒复制所需的激酶与磷酸酶活性之间的精细平衡。