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

Wurm T, Wright DG, Polakowski N, Mesnard JM, Lemasson I - Nucleic Acids Res. (2012)

Bottom Line: This effect correlated with a reduction of H3K18 acetylation, a specific target of p300/CBP, in cells expressing HBZ.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.

View Article: PubMed Central - PubMed

Affiliation: East Carolina University, Brody School of Medicine, Greenville, NC 27834, USA.

ABSTRACT
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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Overexpression of p300 restores H3K18ac in HeLa cells stably expressing HBZ. Immunofluoresence confocal microscopy (magnification ×100/zoom × 1) was used to detect ectopic expression of p300 (denoted by arrows) and to compare levels of H3K18ac in the indicated HeLa cell lines.
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gks244-F4: Overexpression of p300 restores H3K18ac in HeLa cells stably expressing HBZ. Immunofluoresence confocal microscopy (magnification ×100/zoom × 1) was used to detect ectopic expression of p300 (denoted by arrows) and to compare levels of H3K18ac in the indicated HeLa cell lines.

Mentions: To correlate the reduction in H3K18ac with inhibition of p300 HAT activity by HBZ, we tested whether overexpression of p300 would restore H3K18ac in cells expressing HBZ. An expression vector for p300 carrying a C-terminal Flag epitope tag (p300-Flag) was transiently transfected into HeLa cells stably expressing HBZ. Indirect immunofluorescence was then used to identify cells expressing p300-Flag (green) and to assess relative levels of H3K18ac (blue). Figure 4 shows that overexpression of p300 augmented H3K18ac in both cells expressing HBZ and cells carrying the empty vector. Similar levels of H3K18ac were observed in HBZ-expressing cells with p300-Flag and in untransfected cells lacking HBZ. This result indicates that the increased abundance of p300 overwhelmed the ability of HBZ to inhibit HAT activity and reestablished H3K18ac. In contrast to wild-type p300, overexpression of p300 carrying a deletion in the HAT domain did not restore H3K18ac in the presence of HBZ (data not shown).Figure 4.


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

Wurm T, Wright DG, Polakowski N, Mesnard JM, Lemasson I - Nucleic Acids Res. (2012)

Overexpression of p300 restores H3K18ac in HeLa cells stably expressing HBZ. Immunofluoresence confocal microscopy (magnification ×100/zoom × 1) was used to detect ectopic expression of p300 (denoted by arrows) and to compare levels of H3K18ac in the indicated HeLa cell lines.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3401433&req=5

gks244-F4: Overexpression of p300 restores H3K18ac in HeLa cells stably expressing HBZ. Immunofluoresence confocal microscopy (magnification ×100/zoom × 1) was used to detect ectopic expression of p300 (denoted by arrows) and to compare levels of H3K18ac in the indicated HeLa cell lines.
Mentions: To correlate the reduction in H3K18ac with inhibition of p300 HAT activity by HBZ, we tested whether overexpression of p300 would restore H3K18ac in cells expressing HBZ. An expression vector for p300 carrying a C-terminal Flag epitope tag (p300-Flag) was transiently transfected into HeLa cells stably expressing HBZ. Indirect immunofluorescence was then used to identify cells expressing p300-Flag (green) and to assess relative levels of H3K18ac (blue). Figure 4 shows that overexpression of p300 augmented H3K18ac in both cells expressing HBZ and cells carrying the empty vector. Similar levels of H3K18ac were observed in HBZ-expressing cells with p300-Flag and in untransfected cells lacking HBZ. This result indicates that the increased abundance of p300 overwhelmed the ability of HBZ to inhibit HAT activity and reestablished H3K18ac. In contrast to wild-type p300, overexpression of p300 carrying a deletion in the HAT domain did not restore H3K18ac in the presence of HBZ (data not shown).Figure 4.

Bottom Line: This effect correlated with a reduction of H3K18 acetylation, a specific target of p300/CBP, in cells expressing HBZ.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.

View Article: PubMed Central - PubMed

Affiliation: East Carolina University, Brody School of Medicine, Greenville, NC 27834, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus