title: Transcriptional activation of endoplasmic reticulum chaperone GRP78 by HCMV IE1-72 protein.
abstract: 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 1 (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.
authors.affiliation: Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Derick
authors.initials: D
authors.lastname: Shi-Chen Ou
authors.forename: Sung-Bau
authors.initials: SB
authors.lastname: Lee
authors.forename: Chi-Shuen
authors.initials: CS
authors.lastname: Chu
authors.forename: Liang-Hao
authors.initials: LH
authors.lastname: Chang
authors.forename: Bon-chu
authors.initials: BC
authors.lastname: Chung
authors.forename: Li-Jung
authors.initials: LJ
authors.lastname: Juan
mesh_terms: D015153:Blotting, Western; D023081:CCAAT-Binding Factor / Q000378:metabolism; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000235:genetics* / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D035381:TATA-Binding Protein Associated Factors / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D023081:CCAAT-Binding Factor; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D006657:Histones; C088645:IE1 protein, cytomegalovirus; D017874:Immediate-Early Proteins; D018832:Molecular Chaperones; D035381:TATA-Binding Protein Associated Factors