Antiviral inhibition targeting the HCMV kinase pUL97 requires pUL27-dependent degradation of Tip60 acetyltransferase and cell-cycle arrest. Cell Host Microbe 2011 Feb 17;9(2):103-14
Date
02/16/2011Pubmed ID
21320693DOI
10.1016/j.chom.2011.01.006Scopus ID
2-s2.0-79951592516 (requires institutional sign-in at Scopus site) 60 CitationsAbstract
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.
Author List
Reitsma JM, Savaryn JP, Faust K, Sato H, Halligan BD, Terhune SSAuthor
Scott Terhune PhD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antiviral AgentsBenzimidazoles
Cell Cycle
Cell Line
Cyclin-Dependent Kinase Inhibitor p21
Cytomegalovirus
Cytomegalovirus Infections
Down-Regulation
Histone Acetyltransferases
Humans
Lysine Acetyltransferase 5
Phosphotransferases (Alcohol Group Acceptor)
Protein Binding
Protein Kinase Inhibitors
Ribonucleosides
