The Interaction of Herpes Simplex Virus 1 Regulatory Protein ICP22 with the cdc25C Phosphatase Is Enabled In Vitro by Viral Protein Kinases US3 and UL13
The Interaction of Herpes Simplex Virus 1 Regulatory Protein ICP22 with the cdc25C Phosphatase Is Enabled In Vitro by Viral Protein Kinases US3 and UL13
复制标题
DOI：
10.1128/jvi.02022-07
复制
发表时间：
2008-02
影响因子：
5.4
通讯作者：
Benjamin A. Smith-Donald;B. Roizman
中科院分区：
文献类型：
--
作者：
Benjamin A. Smith-Donald;B. Roizman
摘要 早期研究表明，以 UL38、UL41 和 US11 为例的晚期 (γ2) 基因子集的最佳表达需要 ICP22 和 UL13 蛋白激酶，而不是 US3 激酶。在灵长类细胞中，ICP22 介导 cdc2 无活性亚型的消失以及细胞周期蛋白 A 和 B1 的降解。 Active cdc2 获得了一个新伙伴，即病毒 DNA 合成持续性因子 UL42。 cdc2-UL42 复合物招募并磷酸化拓扑异构酶 IIα，以有效表达上面列出的 γ2 基因。在未感染的细胞中，cdc25C 磷酸酶通过去除两个抑制性磷酸盐来激活 cdc2。随附的报告显示，在没有 cdc25C 的情况下，细胞周期蛋白 B1 的降解速率与受感染的野生型小鼠胚胎成纤维细胞中发生的降解速率相似，但 cdc2 的水平增加，并且晚期蛋白子集的积累和病毒产量减少。该报告将 ICP22 与 cdc25C 联系起来。我们发现，在受感染的细胞中，ICP22 和 US3 蛋白激酶介导 cdc25C 在其 C 末端结构域的磷酸化。在使用纯化成分进行的体外测定中，UL13 和 US3 病毒激酶都会磷酸化 cdc25C 和 ICP22。 cdc25C 还与 cdc2 交互。然而，在受感染的细胞中，cdc25C 通过非活性 cdc2 蛋白去磷酸化来激活 cdc2 的能力降低。再加上 US3 激酶对 cdc25C 的磷酸化，结果提出了单纯疱疹病毒 1 改变 cdc25C 执行未感染细胞中执行的功能的可能性。
ABSTRACT Earlier studies have shown that ICP22 and the UL13 protein kinase but not the US3 kinase are required for optimal expression of a subset of late (γ2) genes exemplified by UL38, UL41, and US11. In primate cells, ICP22 mediates the disappearance of inactive isoforms of cdc2 and degradation of cyclins A and B1. Active cdc2 acquires a new partner, the viral DNA synthesis processivity factor UL42. The cdc2-UL42 complex recruits and phosphorylates topoisomerase IIα for efficient expression of the γ2 genes listed above. In uninfected cells, the cdc25C phosphatase activates cdc2 by removing two inhibitory phosphates. The accompanying report shows that in the absence of cdc25C, the rate of degradation of cyclin B1 is similar to that occurring in infected wild-type mouse embryo fibroblast cells but the levels of cdc2 increase, and the accumulation of a subset of late proteins and virus yields are reduced. This report links ICP22 with cdc25C. We show that in infected cells, ICP22 and US3 protein kinase mediate the phosphorylation of cdc25C at its C-terminal domain. In in vitro assays with purified components, both UL13 and US3 viral kinases phosphorylate cdc25C and ICP22. cdc25C also interacts with cdc2. However, in infected cells, the ability of cdc25C to activate cdc2 by dephosphorylation of the inactive cdc2 protein is reduced. Coupled with the phosphorylation of cdc25C by the US3 kinase, the results raise the possibility that herpes simplex virus 1 diverts cdc25C to perform functions other than those performed in uninfected cells.