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

Qiao Jing Lew, Kai Ling Chu, Yi Ling Chia, Benjamin Soo, Jia Pei Ho, Chew Har Ng, Hui Si Kwok, Cheng Ming Chiang, Yao Chang, Sheng Hao Chao

Research output: Contribution to journalArticle

8 Scopus citations

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-1Smediated transcription, including cellular UPR genes and latent membrane protein1 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.

Original languageEnglish (US)
Pages (from-to)271-287
Number of pages17
JournalOncotarget
Volume6
Issue number1
DOIs
StatePublished - 2015

Keywords

  • EBV LMP1
  • GCN5
  • PCAF
  • UPR
  • XBP-1S

ASJC Scopus subject areas

  • Oncology

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    Lew, Q. J., Chu, K. L., Chia, Y. L., Soo, B., Ho, J. P., Ng, C. H., Kwok, H. S., Chiang, C. M., Chang, Y., & Chao, S. H. (2015). GCN5 inhibits XBP-1S-mediated transcription by antagonizing PCAF action. Oncotarget, 6(1), 271-287. https://doi.org/10.18632/oncotarget.2773