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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.

SUBMITTER: Savaryn JP

PROVIDER: S-EPMC3571358 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Human cytomegalovirus pUL29/28 and pUL38 repression of p53-regulated p21CIP1 and caspase 1 promoters during infection.

Savaryn John P JP Reitsma Justin M JM Bigley Tarin M TM Halligan Brian D BD Qian Zhikang Z Yu Dong D Terhune Scott S SS

Journal of virology 20121212 5

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 ...[more]

PMID: 23236067

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Project description:Human cytomegalovirus (HCMV) is a common cause of morbidity and mortality in immunocompromised and immunosuppressed individuals. During infection, HCMV is known to employ host transcription factors to facilitate viral gene expression. To further understand the previously observed delayed viral replication and protein expression in p53 knockout cells, we conducted microarray analyses on p53+/+ and p53-/- immortalized fibroblast cell lines. At 12 hpi, applying the significance criteria defined above, no genes showed a significant difference in any of the comparisons. At 24 hpi, we found 19 genes to be significantly different in the THF versus p53-/- comparison and 14 genes to be significantly different in the HFF versus p53-/- comparison. Eleven genes were shared between HFF and THF cells when compared to p53-/- cells (UL30, UL54, UL63, UL65, UL69, UL75, UL110, UL122, IRL4, IRS1, TRS1, shown in bold in Table 1). Eight genes were unique in the THF versus p53-/- comparison (UL48, UL68, UL84, UL100, UL106, UL109, UL111, RL5A), and three genes in the HFF versus p53-/- cell comparison (UL14, UL16, US2). When comparing HFF and THF cells, only US2 showed a significant difference. The ratio (HFF versus p53-/- divided by THF versus p53-/-) of the expression levels of the eleven shared genes from the HFF versus p53-/- and THF versus p53-/- comparisons was an averaged 1.2, indicating that, with the exception of US2, these two cell lines behaved similarly with respect to p53-driven viral gene expression. Keywords: time course, virus, cytomegalo, hhv5, infection, p53 Each slide consisted of 4 arrays. Each array consisted of 305 control features, 1265 cellular gene features and 670 viral gene features. The study was performed on 6 slides (HFF-THF, HFF-p53-/-, THF-p53-/- at 12 and 24 hpi). 3 arrays per slide were hybridized with 3 biological replicates of labelled RNA, the 4th array was hybridized with an equimolar mixture of the 3 biological replicate samples. This array was used for control purposes only, and the results were not used for downstream calculations. Each slide was stripped and reprobed two times to provide 3 technical replicates of each sample. As our experiments concentrated on viral genes and their expression, cellular genes were not further analyzed in this study.

Dataset Information

Human cytomegalovirus pUL29/28 and pUL38 repression of p53-regulated p21CIP1 and caspase 1 promoters during infection.

Publications

Human cytomegalovirus pUL29/28 and pUL38 repression of p53-regulated p21CIP1 and caspase 1 promoters during infection.

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