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The regulatory role of cyclin-dependent protein kinases in human cytomegalovirus replication

细胞周期蛋白依赖性蛋白激酶在人巨细胞病毒复制中的调节作用

基本信息

批准号：
159234319
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：
2009
资助国家：
德国
起止时间：
2008-12-31 至 2012-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/159234319?language=en
关键词：
regulatory role cyclin dependent protein

项目摘要

Replication of human cytomegalovirus (HCMV) is characterized by a tight virus-host cell interaction, as in particular cyclin-dependent protein kinases (CDKs) are functionally integrated into efficient viral gene expression and protein modification. CDK1, -2, -7 and -9 were identified as main HCMV-regulating kinases, albeit the underlying regulatory mechanisms are still under investigation. We and others reported that pharmacological inhibition of CDK activity induces intranuclear aggregation of the viral regulatory protein pUL69. Interaction analyses showed protein association between pUL69 and CDK/cyclin complexes. Importantly, we demonstrated that CDKs as well as the viral protein kinase pUL97, recently described as a viral CDK ortholog, possess the ability to specifically phosphorylate this viral protein. The functional significance of pUL69 phoshorylation was indicated by the finding that CDK inhibitors reduced its known mRNA export activity. This is the first example defining a specific contact point of the interregulation between CDKs and HCMV replication. The present project will concentrate on the question which functional consequences arise from the CDK inhibitor-induced intranuclear aggregate formation and whether there are further aspects of CDK-HCMV interregulation connected with this finding. In this context, it is suggestive that more viral proteins are involved in the viral CDK interaction, as concluded from preliminary results. Specific experiments will address the compository and functional analysis of heteromeric protein complexes which are associated with CDK inhibitor-induced aggregates. Moreover, mutant viral proteins will be generated to address the question of altered phosphorylation characteristics and the impact of CDK-specific phosphorylation on the activities of these viral proteins. The study will provide a detailed description of the molecular events which recruit CDK activities as an internal pathway of HCMV replication.

人巨细胞病毒（HCMV）复制的特征在于紧密的病毒-宿主细胞相互作用，特别是细胞周期蛋白依赖性蛋白激酶（CDK）在功能上整合到有效的病毒基因表达和蛋白质修饰中。CDK 1、CDK 2、CDK 7和CDK 9被确定为主要的HCMV调节激酶，尽管潜在的调节机制仍在研究中。我们和其他人报道，药物抑制CDK活性诱导病毒调节蛋白pUL 69的核内聚集。相互作用分析表明pUL 69与CDK/cyclin复合物之间存在蛋白质缔合。重要的是，我们证明了CDK以及病毒蛋白激酶pUL 97，最近被描述为病毒CDK直系同源物，具有特异性磷酸化这种病毒蛋白的能力。CDK抑制剂降低其已知mRNA输出活性的发现表明了pUL 69磷酸化的功能意义。这是第一个定义CDK和HCMV复制之间相互调节的特定接触点的例子。本项目将集中在这个问题上的功能性后果所产生的CDK激酶诱导的核内聚集体的形成，以及是否有进一步的方面CDK-HCMV相互调节与这一发现。在这种情况下，这是暗示，更多的病毒蛋白参与病毒CDK相互作用，从初步结果得出的结论。具体的实验将解决与CDK介导的聚集体相关的异聚蛋白复合物的组成和功能分析。此外，将产生突变病毒蛋白，以解决磷酸化特征改变的问题和CDK特异性磷酸化对这些病毒蛋白活性的影响。该研究将提供招募CDK活性作为HCMV复制的内部途径的分子事件的详细描述。