GCN5 inhibits XBP-1S-mediated transcription by antagonizing PCAF action

Abstract

// Qiao Jing Lew 1,* , Kai Ling Chu 1,* , Yi Ling Chia 1 , Benjamin Soo 1 , Jia Pei Ho 1 , Chew Har Ng 1 , Hui Si Kwok 1 , Cheng-Ming Chiang 2 , Yao Chang 3 and Sheng-Hao Chao 1,4 1 Expression Engineering Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore 2 Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Harry Hines Boulevard, Dallas, TX, USA 3 National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan 4 Department of Microbiology, National University of Singapore, Singapore * These authors contributed equally to this work Correspondence: Sheng-Hao Chao, email: // Keywords : XBP-1S, UPR, GCN5, PCAF, EBV LMP1 Received : October 06, 2014 Accepted : November 15, 2014 Published : November 16, 2014 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.