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

人巨细胞病毒（HCMV）复制的特点是病毒与宿主细胞紧密相互作用。特别是，周期蛋白依赖性蛋白激酶（CDKs）在功能上整合到病毒基因表达和蛋白质修饰中。hcmv编码的蛋白激酶pUL97作为CDK同源物，显示出结构和功能上的相似性。最近，我们报道了pUL97激酶与宿主细胞周期蛋白子集之间的相互作用，特别是与细胞周期蛋白T1。pUL97负责与cyclin T1相互作用的序列结构域位于保守激酶结构域外的231-280氨基酸区。在我们正在进行的初步工作中，我们描述了pUL97与细胞周期蛋白B1更明显的相互作用。这一发现是令人惊讶和重要的，因为这是迄今为止发现的唯一一个疱疹病毒激酶-细胞周期蛋白相互作用的例子，可能说明了细胞周期和病毒复制的调节效应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pUL97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，pUL97与细胞周期蛋白B1（而不是细胞周期蛋白T1）之间的相互作用似乎依赖于pUL97的活性，即我们的初步数据表明，用pUL97抑制剂治疗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化分析的结合来研究。特别是，将详细研究pUL97-cyclin相互作用在pUL97磷酸化依赖性调节活性方面的作用。综上所述，确定pUL97-cyclin相互作用在病毒复制背景下的重要性将是至关重要的，它可能对病毒的发病机制产生影响。

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.