Peptidyl-prolyl isomerase Pin1 as a multifunctional regulator of cytomegalovirus replication

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Virus replication is a complex process in general that includes multiple steps of intracellular transport and virion morphogenesis as determined by intense virus-host interaction. In this aspect, recent reports suggested that cellular peptidyl-prolyl isomerases (PPIases) represent a novel group of enzymes that are crucial for efficient replication of various viruses and might be more important than previously expected. In case of herpesviruses, our group has recently provided the first evidence that the cellular isomerase Pin1 facilitates nuclear egress of cytomegaloviral particles. This consequently opens up the intriguing possibility that PPIases might be determinants of virus-host interaction and might even be utilized as novel targets for antiherpesviral strategies. In this project, we will extend our understanding of the role of protein prolyl-isomerization in the regulation of herpesvirus infection. In particular, we intend to characterize important regulatory functions of the PPIase Pin1 during replication of the human and mouse cytomegalovirus. We will address the following questions: (i) is Pin1 activity required for the regulation of distinct steps of the viral replication cycle besides nuclear egress, (ii) which regulatory proteins are subject to Pin1-mediated isomerization in virus-infected cells, and (iii) what are the molecular mechanisms controlling Pin1 activity by the virus? We will additionally develop a microscopy-based assay enabling the analysis of prolyl-isomerization for the first time in living cells. To address these issues, we will use various state-of-the-art techniques including super-resolution STED/RESOLFT microscopy, nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry. The presentedproject will be supported by already fruitful ongoing collaborations and will particularly benefit from the recruitment of further designated experts in their fields. The work programme will specifically help to validate PPIases as novel targets for treatment of herpesviral infections and to develop strategies for future therapeutic interventions.