Epstein-Barr nuclear antigen leader protein coactivates transcription through interaction with histone deacetylase 4.
Epstein-Barr nuclear antigen (EBNA) leader protein (EBNALP) coactivates promoters with EBNA2 and is important for Epstein-Barr virus immortalization of B cells. Investigation of the role of histone deacetylases (HDACs) in EBNALP and EBNA2 promoter regulation has now identified EBNALP and EBNA2 to be associated with HDAC4 in a lymphoblastoid cell line. Furthermore, a transcription-deficient EBNALP point mutant did not associate with HDAC4. HDAC4 and 5 overexpression repressed EBNA2 activation and EBNALP coactivation, whereas other HDACs had little effect. Moreover, EBNALP expression decreased nuclear HDAC4. Expression of 14-3-3 anchors HDAC4 in the cytoplasm, increased EBNALP effects, and reversed HDAC4 or 5 repression. HDAC4 reversal depended on the HDAC4 nuclear export sequence. Consistent with EBNALP coactivation being mediated by nuclear HDAC4 depletion, HDAC4 overexpression increased nuclear HDAC4 and specifically repressed EBNA2-dependent activation as well as EBNALP-dependent coactivation. Also, EBNALP, HDAC4, and 14-3-3 could be immunoprecipitated in a single complex. Thus, these data strongly support a model in which EBNALP coactivates transcription by relocalizing HDAC4 and 5 from EBNA2 activated promoters to the cytoplasm. The observed EBNALP effects are likely also in part through HDAC5, which is highly homologous to HDAC4.
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Department of Microbiology, Brigham and Women's Hospital, Channing Laboratory, Harvard University, Boston, MA 02115, USA.
Rosendorff
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Kieff
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D048948:14-3-3 Proteins / Q000378:metabolism; D001402:B-Lymphocytes / Q000821:virology*; D002458:Cell Fractionation; D045744:Cell Line, Tumor; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics*; D015967:Gene Expression Regulation, Viral / Q000235:genetics*; D005982:Glutathione Transferase; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D021382:Protein Sorting Signals / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology*
D048948:14-3-3 Proteins; D019309:Epstein-Barr Virus Nuclear Antigens; D021382:Protein Sorting Signals; D012097:Repressor Proteins; D005982:Glutathione Transferase; C400300:HDAC4 protein, human; D006655:Histone Deacetylases