title: Human cytomegalovirus pUL29/28 and pUL38 repression of p53-regulated p21CIP1 and caspase 1 promoters during infection.
abstract: During infection by human cytomegalovirus (HCMV), the tumor suppressor protein p53, which promotes efficient viral gene expression, is stabilized. However, the expression of numerous p53-responsive cellular genes is not upregulated. The molecular mechanism used to manipulate the transcriptional activity of p53 during infection remains unclear. The HCMV proteins IE1, IE2, pUL44, and pUL84 likely contribute to the regulation of p53. In this study, we used a discovery-based approach to identify the protein targets of the HCMV protein pUL29/28 during infection. Previous studies have demonstrated that pUL29/28 regulates viral gene expression by interacting with the chromatin remodeling complex NuRD. Here, we observed that pUL29/28 also associates with p53, an additional deacetylase complex, and several HCMV proteins, including pUL38. We confirmed the interaction between p53 and pUL29/28 in both the presence and absence of infection. HCMV pUL29/28 with pUL38 altered the activity of the 53-regulatable p21CIP1 promoter. During infection, pUL29/28 and pUL38 contributed to the inhibition of p21CIP1 as well as caspase 1 expression. The expression of several other p53-regulating genes was not altered. Infection using a UL29-deficient virus resulted in increased p53 binding and histone H3 acetylation at the responsive promoters. Furthermore, expression of pUL29/28 and its interacting partner pUL38 contributed to an increase in the steady-state protein levels of p53. This study identified two additional HCMV proteins, pUL29/28 and pUL38, which participate in the complex regulation of p53 transcriptional activity during infection.
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Savaryn
authors.forename: Justin M
authors.initials: JM
authors.lastname: Reitsma
authors.forename: Tarin M
authors.initials: TM
authors.lastname: Bigley
authors.forename: Brian D
authors.initials: BD
authors.lastname: Halligan
authors.forename: Zhikang
authors.initials: Z
authors.lastname: Qian
authors.forename: Dong
authors.initials: D
authors.lastname: Yu
authors.forename: Scott S
authors.initials: SS
authors.lastname: Terhune
mesh_terms: D000107:Acetylation; D036022:Capsid Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000096:biosynthesis / Q000235:genetics*; D002453:Cell Cycle; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000235:genetics* / Q000378:metabolism / Q000821:virology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D036022:Capsid Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D006657:Histones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; D020170:Caspase 1; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex