Assessing the functional relevance of the isomerase Pin1 for the modulation of herpesviral polymerase complexes

评估异构酶 Pin1 对疱疹病毒聚合酶复合物调节的功能相关性

• 批准号: 501367926
• 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
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/501367926?language=en
• 关键词: Assessing; functional; relevance; isomerase; Pin1

Herpesviruses have evolved a variety of means to recruit cellular regulatory factors to fulfill virus-supportive tasks during replication. In virus-infected cells, protein activity, stability and dynamics of viral and host-derived regulators are frequently modulated by post-translational modifications. The modulation of protein conformations by prolyl isomerases has relevance in early protein biosynthesis as it assures accurate de novo folding. An even more fascinating aspect of isomerases is their regulatory key-role in switching on or off their substrates' functionality through altering protein conformations. This regulatory power was specifically recognized for the phosphorylation-triggered prolyl cis/trans isomerase Pin1, which interacts with human herpesviruses including cytomegalovirus, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. Our latest data substantiate the experimental indications for a regulatory viral kinase–Pin1 interplay and the importance of Pin1 for cytomegalovirus replication efficiency. Particularly, data suggested a virus-mediated recruitment of the Pin1 activity to a selection of target proteins important for viral replication. Hence, the regulatory role of Pin1 was postulated for at least three herpesviral replicative stages, namely (i) its direct binding to viral regulatory proteins, specifically proteins of the viral polymerase complex, (ii) its impact on modulating host factors including signaling and cell cycle regulators, and (iii) its involvement in nuclear lamina rearrangement as a rate-limiting step of viral nuclear egress. In conclusion, Pin1 is considered as a multifaceted host regulator of herpesviruses, and the mechanistic aspects are investigated in this project.

疱疹病毒已经进化出多种手段来募集细胞调节因子以在复制期间完成病毒支持任务。在病毒感染的细胞中，病毒和宿主衍生的调节因子的蛋白质活性、稳定性和动力学经常通过翻译后修饰来调节。脯氨酰异构酶对蛋白质构象的调节与早期蛋白质生物合成有关，因为它确保了准确的从头折叠。异构酶更吸引人的方面是它们的调节关键作用，通过改变蛋白质构象来打开或关闭底物的功能。这种调节能力特别适用于磷酸化触发的脯氨酰顺式/反式异构酶Pin 1，该酶与人类疱疹病毒（包括巨细胞病毒、爱泼斯坦-巴尔病毒和卡波西肉瘤相关疱疹病毒）相互作用。我们的最新数据证实了调节性病毒激酶-Pin 1相互作用的实验适应症以及Pin 1对巨细胞病毒复制效率的重要性。特别是，数据表明病毒介导的招募Pin 1活性的选择，重要的病毒复制的靶蛋白。因此，Pin 1的调节作用被假定为至少三个疱疹病毒复制阶段，即（i）其直接结合病毒调节蛋白，特别是病毒聚合酶复合物的蛋白，（ii）其对调节宿主因子（包括信号传导和细胞周期调节剂）的影响，以及（iii）其参与核纤层重排作为病毒核出口的限速步骤。总之，Pin 1被认为是一个多方面的主机调节疱疹病毒，和机制方面的调查，在这个项目中。