Antagonistic relationship between human cytomegalovirus pUL27 and pUL97 activities during infection

Tarin M. Bigley, Justin M. Reitsma, Scott S. Terhune

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Human cytomegalovirus (HCMV) is a member of the betaherpesvirus family. During infection, an array of viral proteins manipulates the host cell cycle. We have previously shown that expression of HCMV pUL27 results in increased levels of the cyclindependent kinase (CDK) inhibitor p21Cip1. In addition, pUL27 is necessary for the full antiviral activity of the pUL97 kinase inhibitor maribavir (MBV). The purpose of this study was to define the relationship between pUL27 and pUL97 and its role in MBV antiviral activity. We observed that expression of wild-type but not kinase-inactive pUL97 disrupted pUL27-dependent induction of p21Cip1. Furthermore, pUL97 associated with and promoted the phosphorylation of pUL27. During infection, inhibition of the kinase resulted in elevated levels of p21Cip1 in wild-type virus but not a pUL27-deficient virus. We manipulated the p21Cip1 levels to evaluate the functional consequence to MBV. Overexpression of p21Cip1 restored MBV activity against a pUL27- deficient virus, while disruption reduced activity against wild-type virus. We provide evidence that the functional target of p21Cip1 in the context of MBV activity is CDK1. One CDK-like activity of pUL97 is to phosphorylate nuclear lamin A/C, resulting in altered nuclear morphology and increased viral egress. In the presence of MBV, we observed that infection using a pUL27- deficient virus still altered the nuclear morphology. This was prevented by the addition of a CDK inhibitor. Overall, our results demonstrate an antagonistic relationship between pUL27 and pUL97 activities centering on p21Cip1 and support the idea that CDKs can complement some activities of pUL97.

Original languageEnglish
Pages (from-to)10230-10246
Number of pages17
JournalJournal of virology
Volume89
Issue number20
DOIs
StatePublished - 2015

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