title: GCN5 inhibits XBP-1S-mediated transcription by antagonizing PCAF action.
abstract: Cellular unfolded protein response (UPR) is induced when endoplasmic reticulum (ER) is under stress. XBP-1S, the active isoform of X-box binding protein 1 (XBP-1), is a key regulator of UPR. Previously, we showed that a histone acetyltransferase (HAT), p300/CBP-associated factor (PCAF), binds to XBP-1S and functions as an activator of XBP-1S. Here, we identify general control nonderepressible 5 (GCN5), a HAT with 73% identity to PCAF, as a novel XBP-1S regulator. Both PCAF and GCN5 bind to the same domain of XBP-1S. Surprisingly, GCN5 potently blocks the XBP-1S-mediated transcription, including cellular UPR genes and latent membrane protein 1 of Epstein-Barr virus. Unlike PCAF, GCN5 acetylates XBP-1S and enhances nuclear retention and protein stability of XBP-1S. However, such GCN5-mediated acetylation of XBP-1S shows no effects on XBP-1S activity. In addition, the HAT activity of GCN5 is not required for repression of XBP-1S target genes. We further demonstrate that GCN5 inhibits XBP-1S-mediated transcription by disrupting the PCAF-XBP-1S interaction and preventing the recruitment of XBP-1S to its target genes. Taken together, our results represent the first work demonstrating that GCN5 and PCAF exhibit different functions and antagonistically regulate the XBP-1S-mediated transcription.
authors.affiliation: Expression Engineering Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Qiao Jing
authors.initials: QJ
authors.lastname: Lew
authors.affiliation: Expression Engineering Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Kai Ling
authors.initials: KL
authors.lastname: Chu
authors.affiliation: Expression Engineering Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Yi Ling
authors.initials: YL
authors.lastname: Chia
authors.affiliation: Expression Engineering Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Soo
authors.affiliation: Expression Engineering Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Jia Pei
authors.initials: JP
authors.lastname: Ho
authors.affiliation: Expression Engineering Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Chew Har
authors.initials: CH
authors.lastname: Ng
authors.affiliation: Expression Engineering Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Hui Si
authors.initials: HS
authors.lastname: Kwok
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Harry Hines Boulevard, Dallas, TX, USA.
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chiang
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chang
authors.affiliation: Expression Engineering Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore. Department of Microbiology, National University of Singapore, Singapore.
authors.forename: Sheng-Hao
authors.initials: SH
authors.lastname: Chao
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D006801:Humans; D047468:Immunoprecipitation; D016133:Polymerase Chain Reaction; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000502:physiology*; D014162:Transfection; D000071717:X-Box Binding Protein 1; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C000605543:XBP1 protein, human