Abstract
X-box binding protein 1 (XBP1) is a member of the CREB/ATF basic region leucine zipper family transcribed as the unspliced isoform (XBP1-u), which, upon exposure to endoplasmic reticulum stress, is spliced into its spliced isoform (XBP1-s). XBP1-s interacts with the cAMP response element of major histocompatibility complex class II gene and plays critical role in unfolded protein response (UPR) by regulating the transcriptional activity of genes involved in UPR. XBP1-s is also involved in other physiological pathways, including lipid metabolism, insulin metabolism, and differentiation of immune cells. Its aberrant expression is closely related to inflammation, neurodegenerative disease, viral infection, and is crucial for promoting tumor progression and drug resistance. Meanwhile, recent studies reported that the function of XBP1-u has been underestimated, as it is not merely a precursor of XBP1-s. Instead, XBP-1u is a critical factor involved in various biological pathways including autophagy and tumorigenesis through post-translational regulation. Herein, we summarize recent research on the biological functions of both XBP1-u and XBP1-s, as well as their relation to diseases.
Highlights
X-box binding protein 1 (XBP1), which belongs to the basic leucine zipperprotein family, was first isolated in human B lymphoblastoid cell lines during a screening for key genes that regulate major histocompatibility complex (MHC) class II molecules using a human B cell cDNA expression library with an X-box target sequence [1]
We showed that without exposure to endoplasmic reticulum (ER) stressors such as hypoxia and nutrient deficiency, XBP1-u is the major form of XBP1 in tumor cells and is crucial for regulating p53 protein stability at the post-translational stage
XBP1-s is negatively correlated with poor prognosis and low survival of pulmonary adenocarcinoma, colon carcinoma, and gallbladder cancer patients [114,115,129], further supporting the view that increased XBP1-s expression contributes to the acquisition of Epithelial–mesenchymal transition (EMT) phenotype and tumor metastasis
Summary
X-box binding protein 1 (XBP1), which belongs to the basic leucine zipper (bZIP). protein family, was first isolated in human B lymphoblastoid cell lines during a screening for key genes that regulate major histocompatibility complex (MHC) class II molecules using a human B cell cDNA expression library with an X-box target sequence [1]. XBP1-s is produced upon exposure to endoplasmic reticulum (ER) stress resulting from changes in extrinsic and intrinsic factors, including microenvironment, overproduction of reactive oxygen species (ROS), excessive proliferation, and viral infection. Since emerging evidence has revealed that XBP1-u is not merely a precursor of XBP1-s, but is a critical factor in various biological pathways, such as protection of endothelial cells from oxidative stress, regulation of the cell cycle, and vascular calcification, and functions in an XBP1-s independent manner [10–13]. These studies pointed out the special, unique functions of XBP1-u through mechanisms distinct from those of XBP1-s. We will outline the structural and functional differences between XBP1u and XBP1-s, as well as their physiological and pathological functions, especially in the regulation of metabolism, differentiation, inflammation, neurodegenerative diseases, and tumor progression
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