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

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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.