Portal D, Rosendorff A, Kieff E
Department of Microbiology, Brigham and Women's Hospital, Channing Laboratory, Harvard University, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19278-83. doi: 10.1073/pnas.0609320103. Epub 2006 Dec 11.
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.
爱泼斯坦-巴尔核抗原（EBNA）前导蛋白（EBNALP）与EBNA2共同激活启动子，对爱泼斯坦-巴尔病毒使B细胞永生化很重要。对组蛋白去乙酰化酶（HDACs）在EBNALP和EBNA2启动子调控中作用的研究现已确定，在一个淋巴母细胞系中EBNALP和EBNA2与HDAC4相关联。此外，一个转录缺陷型的EBNALP点突变体不与HDAC4相关联。HDAC4和5的过表达抑制了EBNA2的激活和EBNALP的共激活，而其他HDACs几乎没有影响。而且，EBNALP的表达降低了细胞核内的HDAC4。14-3-3的表达将HDAC4锚定在细胞质中，增强了EBNALP的作用，并逆转了HDAC4或5的抑制作用。HDAC4的逆转依赖于HDAC4的核输出序列。与EBNALP的共激活是由细胞核内HDAC4的耗竭介导的一致，HDAC4的过表达增加了细胞核内的HDAC4，并特异性地抑制了EBNA2依赖的激活以及EBNALP依赖的共激活。此外，EBNALP、HDAC4和14-3-3可以在一个单一复合物中被免疫沉淀。因此，这些数据有力地支持了一个模型，即EBNALP通过将HDAC4和5从EBNA2激活的启动子重新定位到细胞质中来共激活转录。观察到的EBNALP效应可能也部分是通过HDAC5，它与HDAC4高度同源。
