title: Functional interaction of the human cytomegalovirus IE2 protein with histone deacetylase 2 in infected human fibroblasts.
abstract: In human cytomegalovirus (HCMV)-infected cells, the 86 kDa immediate-early (IE) 2 protein plays a key role in transactivating downstream viral genes. Recently, IE2 has been shown to interact with histone deacetylase 1 (HDAC1) and HDAC3. HDAC1 recruited by IE2 was required for IE2-mediated autorepression of the major IE (MIE) promoter, whereas IE2-HDAC3 interaction was suggested to relieve the repressive effect of HDAC3 on viral early promoters. However, whether IE2 indeed inhibits HDAC's deacetylation activity on viral promoters and interacts with other HDACs remains unclear. Here, we provide evidence that IE2 functionally interacts with HDAC2 and negates its repressive effect on the viral polymerase promoter. IE2 interacted with HDAC2 in both virus-infected cells and in vitro, and required the conserved C-terminal half for HDAC2 binding. The subcellular localization of HDAC2 was changed in virus-infected cells, showing colocalization with IE2 in viral transcription and replication sites. The overall HDAC2 protein levels and its deacetylation activity slightly increased during the late stages of infection and the IE2-associated deacetylation activity was still sensitive to an HDAC inhibitor, trichostatin A. In transfection assays, however, histone acetylation of the viral polymerase promoter was suppressed by HDAC2, and this was relieved by IE2 binding. Therefore, our data demonstrate that IE2 functionally interacts with HDAC2 and modulates its deacetylation activity on the viral polymerase promoter. Our results also support the idea that interactions of IE2 with several HDACs to modulate the host epigenetic regulation on viral MIE and early promoters are important events in the process of productive infection.
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
authors.forename: Jung-Jin
authors.initials: JJ
authors.lastname: Park
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
authors.forename: Young-Eui
authors.initials: YE
authors.lastname: Kim
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
authors.forename: Hong Thanh
authors.initials: HT
authors.lastname: Pham
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
authors.forename: Eui Tae
authors.initials: ET
authors.lastname: Kim
authors.affiliation: Department of Nanomedical Engineering, Pusan National University, Miryang, Republic of Korea.
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Chung
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
authors.forename: Jin-Hyun
authors.initials: JH
authors.lastname: Ahn
mesh_terms: D000107:Acetylation; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000821:virology*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000821:virology; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: D006877:Hydroxamic Acids; C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; C109367:UL54 protein, Human herpesvirus 5; D014764:Viral Proteins; C012589:trichostatin A; D004259:DNA-Directed DNA Polymerase; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases