Regulatory interaction between cellular cyclins and the cyclin-dependent protein kinase ortholog pUL97 of human cytomegalovirus

细胞周期蛋白和人巨细胞病毒的周期蛋白依赖性蛋白激酶直系同源物 pUL97 之间的调节相互作用

• 批准号: 280194832
• 负责人: Professor Dr. Manfred Marschall
• 金额: --
• 依托单位: Virologisches Institut - Klinische und Molekulare Virologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280194832?language=en
• 关键词: Regulatory; interaction; between; cellular; cyclins

Replication of human cytomegalovirus (HCMV) is characterized by a tight virus-host cell interaction. In particular, cyclin-dependent protein kinases (CDKs) are functionally integrated into viral gene expression and protein modification. The HCMV-encoded protein kinase pUL97 acts as a CDK ortholog showing structural and functional similarities. Recently, we reported an interaction between pUL97 kinase with a subset of host cyclins, in particular with cyclin T1. The sequence domain of pUL97 responsible for the interaction with cyclin T1 was identified in the amino acid region 231-280 lying outside the conserved kinase domain. In our ongoing preliminary work, we describe an even more pronounced interaction of pUL97 with cyclin B1. The finding is surprising and important regarding that this is the only example of a herpesviral kinase-cyclin interaction identified so far that may illustrate a cross-talk between cyclins representing regulatory effectors of the cell cycle and viral replication. Importantly, we were able to demonstrate that the HCMV-encoded kinase pUL97 does not exclusively bind to one cyclin but undergoes interactions with several types of cyclins, which is reminiscent to the variable combinations of CDK-cyclin interactions. As a striking feature, the interaction between pUL97 and cyclin B1 (but not cyclin T1) seems to be dependent on pUL97 activity, i.e. our preliminary data suggest a block of cyclin B1 interaction by treatment with pUL97 inhibitors. Thus, the mechanism of interaction is scientifically challenging and will be studied by a combination of bioinformatics and biochemical analyses. Especially, the role of the pUL97-cyclin interaction, in regard of phosphorylation-dependent regulatory activities of pUL97, will be investigated in detail. Combined, it will be fundamental to ascertain the importance of pUL97-cyclin interaction in the context of viral replication possessing a putative impact on viral pathogenesis.

人巨细胞病毒（HCMV）复制的特点是病毒与宿主细胞的紧密相互作用。特别是，细胞周期蛋白依赖性蛋白激酶（CDK）功能整合到病毒基因表达和蛋白质修饰。HCMV编码的蛋白激酶pUL 97作为CDK直系同源物，显示出结构和功能的相似性。最近，我们报道了pUL 97激酶与宿主细胞周期蛋白的一个子集，特别是与细胞周期蛋白T1之间的相互作用。在位于保守激酶结构域之外的氨基酸区域231-280中鉴定了负责与细胞周期蛋白T1相互作用的pUL 97的序列结构域。在我们正在进行的初步工作中，我们描述了一个更明显的pUL 97与细胞周期蛋白B1的相互作用。这一发现是令人惊讶的和重要的，因为这是迄今为止鉴定的疱疹病毒激酶-细胞周期蛋白相互作用的唯一实例，其可以说明代表细胞周期和病毒复制的调节效应物的细胞周期蛋白之间的串扰。重要的是，我们能够证明HCMV编码的激酶pUL 97并不只与一种细胞周期蛋白结合，而是与几种类型的细胞周期蛋白相互作用，这让人想起CDK-细胞周期蛋白相互作用的可变组合。作为一个显著的特征，pUL 97和细胞周期蛋白B1（而不是细胞周期蛋白T1）之间的相互作用似乎依赖于pUL 97的活性，即我们的初步数据表明用pUL 97抑制剂处理可以阻断细胞周期蛋白B1的相互作用。因此，相互作用的机制在科学上具有挑战性，将通过生物信息学和生物化学分析相结合来研究。特别是，pUL 97-细胞周期蛋白相互作用的作用，在pUL 97的磷酸化依赖性调节活动方面，将详细研究。结合，这将是根本的，以确定的重要性，pUL 97细胞周期蛋白的相互作用的背景下，病毒复制拥有一个假定的影响病毒的发病机制。