PCAF interacts with XBP-1S and mediates XBP-1S-dependent transcription

Lew, Qiao Jing; Chu, Kai Ling; Lee, Jialing; Koh, Poh Ling; Rajasegaran, Vikneswari; Teo, Jin Yuan; Chao, Sheng-Hao

INTRODUCTION X-box binding protein 1 (XBP-1) belongs to the cyclic AMP response element binding protein/activating transcription factor (CREB/ATF) family of transcription factors. XBP-1 plays a major role in regulating unfolded protein response (UPR), which is triggered when endoplasmic reticulum (ER) is under stress (1) . XBP-1 has two protein isoforms, XBP-1U and XBP-1S. Both isoforms share a common N-terminus containing a basic-region leucine zipper (bZIP) domain which is required for DNA binding. XBP-1U is the dominant isoform under non-stress conditions. Activation of UPR induces the endoribonuclease activity of inositol requiring enzyme 1, an ER transmembrane protein, which removes 26 nts from the open-reading frame of XBP-1 mRNA (2) . This unconventional splicing occurs in cytoplasm and causes a frame shift at amino acid 165 of XBP-1, leading to the generation of XBP-1S by replacing the C-terminus of XBP-1U with a strong transactivation domain (2, 3) . XBP-1S is a transcription activator that up-regulates the expression of ER chaperones and other genes involved in membrane synthesis and the pathway of protein secretion (4, 5) . Overexpression of XBP-1S increases the secretory capacity of the cell and improves recombinant protein productivity in secretion-limited mammalian cells by expanding the surface area and volume of ER (5, 6) . It has been shown recently that high-level expression of recombinant secreted proteins in cells and environmental stresses during culture also induce the generation of XBP-1S (7) . XBP-1S is also found to be essential in the terminal differentiation of the antibody producing plasma cells by enhancing the secretory machinery of the cell (8, 9) . The XBP-1-knockout B cells display impaired immunoglobulin secretion, which can be restored by ectopic expression of XBP-1S (8) . Furthermore, the involvement of XBP-1 in tumorigenesis has been reported recently (10) (11) (12) .