Antiviral inhibition targeting the HCMV kinase pUL97 requires pUL27-dependent degradation of Tip60 acetyltransferase and cell-cycle arrest

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...

Full description

Saved in:
Bibliographic Details
Published in:Cell host & microbe 2011-02, Vol.9 (2), p.103-114
Main Authors: Reitsma, Justin M, Savaryn, John Paul, Faust, Katherine, Sato, Hiromi, Halligan, Brian D, Terhune, Scott S
Format: Article
Language:English
Subjects:
Antiviral Agents - pharmacology
Benzimidazoles - pharmacology
Cell Cycle - drug effects
Cell Line
Cyclin-Dependent Kinase Inhibitor p21 - genetics
Cyclin-Dependent Kinase Inhibitor p21 - metabolism
Cytomegalovirus - drug effects
Cytomegalovirus - enzymology
Cytomegalovirus - genetics
Cytomegalovirus - physiology
Cytomegalovirus Infections - enzymology
Cytomegalovirus Infections - physiopathology
Cytomegalovirus Infections - virology
Down-Regulation - drug effects
Histone Acetyltransferases - genetics
Histone Acetyltransferases - metabolism
Humans
Lysine Acetyltransferase 5
Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors
Phosphotransferases (Alcohol Group Acceptor) - genetics
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Protein Binding
Protein Kinase Inhibitors - pharmacology
Ribonucleosides - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1931-3128
1934-6069
DOI:10.1016/j.chom.2011.01.006