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 language | English (US) |
---|---|
Pages (from-to) | 271-287 |
Number of pages | 17 |
Journal | Oncotarget |
Volume | 6 |
Issue number | 1 |
State | Published - 2015 |
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Keywords
- EBV LMP1
- GCN5
- PCAF
- UPR
- XBP-1S
ASJC Scopus subject areas
- Oncology
Cite this
GCN5 inhibits XBP-1S-mediated transcription by antagonizing PCAF action. / Lew, Qiao Jing; Chu, Kai Ling; Chia, Yi Ling; Soo, Benjamin; Ho, Jia Pei; Ng, Chew Har; Kwok, Hui Si; Chiang, Cheng Ming; Chang, Yao; Chao, Sheng Hao.
In: Oncotarget, Vol. 6, No. 1, 2015, p. 271-287.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - GCN5 inhibits XBP-1S-mediated transcription by antagonizing PCAF action
AU - Lew, Qiao Jing
AU - Chu, Kai Ling
AU - Chia, Yi Ling
AU - Soo, Benjamin
AU - Ho, Jia Pei
AU - Ng, Chew Har
AU - Kwok, Hui Si
AU - Chiang, Cheng Ming
AU - Chang, Yao
AU - Chao, Sheng Hao
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - EBV LMP1
KW - GCN5
KW - PCAF
KW - UPR
KW - XBP-1S
UR - http://www.scopus.com/inward/record.url?scp=84921405901&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84921405901&partnerID=8YFLogxK
M3 - Article
C2 - 25426559
AN - SCOPUS:84921405901
VL - 6
SP - 271
EP - 287
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 1
ER -