The HTLV-1-encoded protein HBZ directly inhibits the acetyl transferase activity of p300/CBP

Nucleic Acids Research, Jul 2012

The homologous cellular coactivators p300 and CBP contain intrinsic lysine acetyl transferase (termed HAT) activity. This activity is responsible for acetylation of several sites on the histones as well as modification of transcription factors. In a previous study, we found that HBZ, encoded by the Human T-cell Leukemia Virus type 1 (HTLV-1), binds to multiple domains of p300/CBP, including the HAT domain. In this study, we found that HBZ inhibits the HAT activity of p300/CBP through the bZIP domain of the viral protein. This effect correlated with a reduction of H3K18 acetylation, a specific target of p300/CBP, in cells expressing HBZ. Interestingly, lower levels of H3K18 acetylation were detected in HTLV-1 infected cells compared to non-infected cells. The inhibitory effect of HBZ was not limited to histones, as HBZ also inhibited acetylation of the NF-κB subunit, p65, and the tumor suppressor, p53. Recent studies reported that mutations in the HAT domain of p300/CBP that cause a defect in acetylation are found in certain types of leukemia. These observations suggest that inhibition of the HAT activity by HBZ is important for the development of adult T-cell leukemia associated with HTLV-1 infection.

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The HTLV-1-encoded protein HBZ directly inhibits the acetyl transferase activity of p300/CBP

Torsten Wurm 0 Diana G. Wright 0 Nicholas Polakowski 0 Jean-Michel Mesnard Isabelle Lemasson 0 0 East Carolina University, Brody School of Medicine , Greenville, NC 27834, USA The homologous cellular coactivators p300 and CBP contain intrinsic lysine acetyl transferase (termed HAT) activity. This activity is responsible for acetylation of several sites on the histones as well as modification of transcription factors. In a previous study, we found that HBZ, encoded by the Human T-cell Leukemia Virus type 1 (HTLV-1), binds to multiple domains of p300/CBP, including the HAT domain. In this study, we found that HBZ inhibits the HAT activity of p300/CBP through the bZIP domain of the viral protein. This effect correlated with a reduction of H3K18 acetylation, a specific target of p300/CBP, in cells expressing HBZ. Interestingly, lower levels of H3K18 acetylation were detected in HTLV-1 infected cells compared to non-infected cells. The inhibitory effect of HBZ was not limited to histones, as HBZ also inhibited acetylation of the NF-iB subunit, p65, and the tumor suppressor, p53. Recent studies reported that mutations in the HAT domain of p300/ CBP that cause a defect in acetylation are found in certain types of leukemia. These observations suggest that inhibition of the HAT activity by HBZ is important for the development of adult T-cell leukemia associated with HTLV-1 infection. - In mammalian cells, the coactivators p300 and CBP, also called KAT3B and KAT3A, respectively, play an essential role in transcription. These ubiquitously-expressed proteins are highly homologous and frequently referred to singularly as p300/CBP. They are recruited to promoters or enhancers through interactions with numerous transcription factors where they engage additional regulators and bridge transcription factors to the general transcription machinery (1). The widespread use of p300 and CBP in transcription is due to the presence of multiple, independent domains in these coactivators (2) that, together, contact more than 400 transcriptional regulators in the cell (3). p300/CBP also carries a lysine acetyl transferase activity (classically designated histone acetyl transferase or HAT activity) that acetylates both histones (4,5) and transcription factors (6). Acetylation of lysine residues within the N-terminal tails as well as the globular domains of the histones is generally linked to active transcription (7,8). In contrast, acetylation of transcription factors produces both positive and negative effects on activity by influencing such properties as cellular localization, stability and molecular interactions (9). p300/ CBP is capable of acetylating several core histone lysine residues (10), many of which are also targeted by other proteins with acetyl transferase activity (10,11). However, recent data indicate that lysines 18 and 27 of histone H3 (H3K18ac and H3K27ac) are distinctly acetylated by p300/CBP, as depletion of both coactivators in mouse embryonic fibroblasts leads to a reduction in these modifications (12). In addition, p300/CBP also specifically acetylates lysine 56 of H3 during the DNA damage response (13). Accumulating evidence indicates that CBP and, to a lesser extent p300, function as tumor suppressors. Mutations in p300 and CBP have been identified in many types of cancer (14). In mice, deletion of a single allele of the CBP gene produces defects in hematopoietic differentiation and an increased incidence of hematologic malignancies (15), while homozygous deletion of the gene causes embryonic lethality (16), In humans, deletions or mutations within a single allele of the CREBBP or EP300 gene is sufficient to cause RubensteinTaybi syndrome, which is associated with a high frequency of tumor development among other clinical manifestations (17). Therefore, in mice and humans, p300 and CBP appear limiting in the cell, and a reduction in their functional activities may lead to transformation. Recent studies show that disruption of p300/CBP HAT activity, specifically, may play a primary role in certain hematological transformation events. Indeed, mutations in CBP and p300 that disrupt HAT activity were found to be prevalent in cases of diffuse large B-cell lymphoma (18,19) and follicular carcinoma (1820). In relapsed acute lymphoblastic leukemia, the CREBBP gene is also frequently mutated or deleted such that HAT activity is repressed (21). Interestingly, for some types of cancer, a global reduction in the level of H3K18ac serves as a prognostic indicator of a poor clinical outcome (2228). These observations indicate that p300/CBP HAT activity is targeted during transformation. Human T-cell Leukemia Virus type 1 (HTLV-1) is a complex retrovirus that causes adult T-cell leukemia/ lymphoma (ATL), a malignancy characterized by the abnormal proliferation of mature CD4+ cells (29,30). ATL is a heterogeneous disease with different clinical stages. The acute and lymphoma subtypes are the most aggressive forms of ATL, (...truncated)


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Torsten Wurm, Diana G. Wright, Nicholas Polakowski, Jean-Michel Mesnard, Isabelle Lemasson. The HTLV-1-encoded protein HBZ directly inhibits the acetyl transferase activity of p300/CBP, Nucleic Acids Research, 2012, pp. 5910-5925, 40/13, DOI: 10.1093/nar/gks244