title: Regulatory roles of protein kinases in cytomegalovirus replication.
abstract: Viral replication is a complex process relying on a network of interacting viral and cellular proteins, in which particularly protein kinases play an important regulatory role. The specific phosphorylation of substrate proteins induces activation, inactivation, or other functional modification and thus determines virus-host cell interregulation. During herpesviral infections, both viral and cellular protein kinases are expressed and provide activities crucial for the efficiency of virus replication. The protein kinase pUL97 encoded by human cytomegalovirus (HCMV) is a multifunctional regulatory enzyme which exerts strong regulatory effects on early and late steps of the viral replication cycle. A number of interacting proteins and substrates of pUL97 have been described, including retinoblastoma (Rb) protein, nuclear lamins and viral pUL69. Recently, it was demonstrated that pUL97 has structural and functional resemblance to cyclin-dependent protein kinases (CDKs) and thus represents a CDK ortholog. pUL97 can phosphorylate and inactivate Rb, resulting in a stimulation of cell cycle progression. In addition, the association of pUL97 activity with nucleocytoplasmic export of viral capsids has been demonstrated by several investigators. We could show that pUL97 is able to phosphorylate nuclear lamins and to contribute to the HCMV-induced reorganization of the nuclear lamina. On the basis of very recent findings, it is becoming increasingly clear that pUL97 is a component of a multiprotein nuclear egress complex (NEC). The NEC contains a small number of egress proteins involved in the recruitment of protein kinases, such as pUL97 and cellular protein kinase C (PKC), to specific sites of the nuclear lamina. Current information about the composition, function, and regulatory complexity of the NEC leads to a mechanistic concept which may set the key features of HCMV nuclear egress in a new light.
authors.affiliation: Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Marschall
authors.forename: Sabine
authors.initials: S
authors.lastname: Feichtinger
authors.forename: Jens
authors.initials: J
authors.lastname: Milbradt
mesh_terms: D000818:Animals; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D003587:Cytomegalovirus / Q000201:enzymology / Q000235:genetics* / Q000502:physiology; D015967:Gene Expression Regulation, Viral; D006566:Herpesviridae Infections / Q000473:pathology / Q000821:virology; D006801:Humans; D034881:Nuclear Lamina / Q000235:genetics / Q000378:metabolism / Q000821:virology; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D012175:Retinoblastoma / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D011493:Protein Kinase C; D018844:Cyclin-Dependent Kinases