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A conserved gammaherpesvirus protein kinase targets histone deacetylases 1 and 2 to facilitate viral replication in primary macrophages. J Virol 2013 Jul;87(13):7314-25

Date

04/26/2013

Pubmed ID

23616648

Pubmed Central ID

PMC3700300

DOI

10.1128/JVI.02713-12

Abstract

Gammaherpesviruses are ubiquitious pathogens that establish lifelong infection and are associated with several malignancies. All gammaherpesviruses encode a conserved protein kinase that facilitates viral replication and chronic infection and thus represents an attractive therapeutic target. In this study, we identify a novel function of gammaherpesvirus protein kinase as a regulator of class I histone deacetylases (HDAC). Mouse gammaherpesvirus 68 (MHV68)-encoded protein kinase orf36 interacted with HDAC1 and 2 and prevented association of these HDACs with the viral promoter driving expression of RTA, a critical immediate early transcriptional activator. Furthermore, the ability to interact with HDAC1 and 2 was not limited to the MHV68 orf36, as BGLF4, a related viral protein kinase encoded by Epstein-Barr virus, interacted with HDAC1 in vitro. Importantly, targeting of HDAC1 and 2 by orf36 was independent of the kinase's enzymatic activity. Additionally, orf36 expression, but not its enzymatic activity, induced changes in the global deacetylase activity observed in infected primary macrophages. Combined deficiency of HDAC1 and 2 rescued attenuated replication and viral DNA synthesis of the orf36 null MHV68 mutant, indicating that the regulation of HDAC1 and 2 by orf36 was relevant for viral replication. Understanding the mechanism by which orf36 facilitates viral replication, including through HDAC targeting, will facilitate the development of improved therapeutics against gammaherpesvirus kinases.

Author List

Mounce BC, Mboko WP, Bigley TM, Terhune SS, Tarakanova VL

Authors

Vera Tarakanova PhD Associate Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Scott Terhune PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Blotting, Western
Chromatin Immunoprecipitation
DNA Primers
Fluorescent Antibody Technique
Gammaherpesvirinae
Histone Deacetylases
Immunoprecipitation
Macrophages
Mice
Mice, Inbred C57BL
Protein Kinases
Protein-Serine-Threonine Kinases
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Viral Proteins
Virus Replication
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