The HTLV-1-encoded protein HBZ directly inhibits the acetyl transferase activity of p300/CBP
Torsten Wurm
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Diana G. Wright
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Nicholas Polakowski
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Jean-Michel Mesnard
Isabelle Lemasson
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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.
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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)