1. Antiviral inhibition targeting the HCMV kinase pUL97 requires pUL27-dependent degradation of Tip60 acetyltransferase and cell-cycle arrest.
- Author
-
Reitsma JM, Savaryn JP, Faust K, Sato H, Halligan BD, and Terhune SS
- Subjects
- Benzimidazoles pharmacology, Cell Line, Cyclin-Dependent Kinase Inhibitor p21 genetics, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Cytomegalovirus drug effects, Cytomegalovirus genetics, Cytomegalovirus physiology, Cytomegalovirus Infections physiopathology, Cytomegalovirus Infections virology, Down-Regulation drug effects, Histone Acetyltransferases genetics, Humans, Lysine Acetyltransferase 5, Phosphotransferases (Alcohol Group Acceptor) genetics, Phosphotransferases (Alcohol Group Acceptor) metabolism, Protein Binding, Ribonucleosides pharmacology, Antiviral Agents pharmacology, Cell Cycle drug effects, Cytomegalovirus enzymology, Cytomegalovirus Infections enzymology, Histone Acetyltransferases metabolism, Phosphotransferases (Alcohol Group Acceptor) antagonists & inhibitors, Protein Kinase Inhibitors pharmacology
- Abstract
Infection with the β-herpesvirus human cytomegalovirus (HCMV) is lifelong, causing limited disease in healthy adults, but life threatening in immunocompromised individuals. The viral kinase pUL97, a functional ortholog of cellular cyclin-dependent kinases (CDKs), is critical for HCMV replication and a target for antiviral drug development. Upon kinase inhibition, drug-resistant strains emerge with mutations in UL27, an HCMV gene of unknown function. Using a proteomics approach, we discovered that pUL27 is necessary and sufficient to degrade Tip60, a host acetyltransferase and interacting partner of HIV Tat. Consistent with this, the expression of Tat restored antiviral inhibition of an otherwise resistant HCMV strain. The functional consequence of Tip60 degradation was the induction of the CDK inhibitor p21(Waf1/Cip1) and cell-cycle arrest, representing changes necessary for the antiviral effects of pUL97 inhibition. Consequently, either increasing p21(Waf1/Cip1) expression or decreasing Tip60 levels improved the antiviral activity of the HCMV kinase inhibitor maribavir., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF