Transcriptional activation of endoplasmic reticulum chaperone GRP78 by HCMV IE1-72 protein

• Published in: Cell research 2011-04, Vol.21 (4), p.642-653
• Main Authors: Shi-Chen Ou, Derick, Lee, Sung-Bau, Chu, Chi-Shuen, Chang, Liang-Hao, Chung, Bon-chu, Juan, Li-Jung
• Format: Article
• Language: English
• Subjects: 631/208/200; 631/80/470/1981; 631/80/642/1463; 692/699/255/2514; ATP; Biomedical and Life Sciences; Blotting, Western; CCAAT-Binding Factor - metabolism; Cell Biology; Cell Line; Chromatin Immunoprecipitation; Cytomegalovirus - genetics; Cytomegalovirus - metabolism; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - metabolism; Gene Expression; HCMV; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Histones - metabolism; Humans; Immediate-Early Proteins - metabolism; Life Sciences; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Original; original-article; Polymerase Chain Reaction; Promoter Regions, Genetic; TATA-Binding Protein Associated Factors - metabolism; Transcriptional Activation; 人巨细胞病毒; 内质网; 分子伴侣; 染色质结构; 组蛋白乙酰转移酶; 调节蛋白; 转录激活
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2011.10

Glucose-regulated protein 78 （GRP78）, a key regulator of endoplasmic reticulum （ER） stress, facilitates cancer cell growth and viral replication. The mechanism leading to grp78 gene activation during viral infection is largely unknown. In this study, we show that the immediate-early 1 （IE1-72） protein of the human cytomegalovirus （HCMV） is essential for HCMV-mediated GRP78 activation. IE1-72 upregulated grp78 gene expression depending on the ATP- binding site, the zinc-finger domain and the putative leucine-zipper motif of IE1-72, as well as the ER stress response elements （ERSEs） on the grp78 promoter. The purified IE1-72 protein bound to the CCAAT box within ERSE in vitro, whereas deletion mutants of IE1-72 deficient in grp78 promoter stimulation failed to do so. Moreover, IE1-72 binding to the grp78 promoter in infected cells accompanied the recruitment of TATA box-binding protein-associated factor I （TAF1）, a histone acetyltransferase, and the increased level of acetylated histone H4, an indicator of active- state chromatin. These results provide evidence that HCMV IE1-72 activates grp78 gene expression through direct promoter binding and modulation of the local chromatin structure, indicating an active viral mechanism of cellular chaperone induction for viral growth.