Abstract
The spliced form of X-box binding protein 1 (XBP1s) is an active transcription factor that plays a vital role in the unfolded protein response (UPR). Under endoplasmic reticulum (ER) stress, unspliced Xbp1 mRNA is cleaved by the activated stress sensor IRE1α and converted to the mature form encoding spliced XBP1 (XBP1s). Translated XBP1s migrates to the nucleus and regulates the transcriptional programs of UPR target genes encoding ER molecular chaperones, folding enzymes, and ER-associated protein degradation (ERAD) components to decrease ER stress. Moreover, studies have shown that XBP1s regulates the transcription of diverse genes that are involved in lipid and glucose metabolism and immune responses. Therefore, XBP1s has been considered an important therapeutic target in studying various diseases, including cancer, diabetes, and autoimmune and inflammatory diseases. XBP1s is involved in several unique mechanisms to regulate the transcription of different target genes by interacting with other proteins to modulate their activity. Although recent studies discovered numerous target genes of XBP1s via genome-wide analyses, how XBP1s regulates their transcription remains unclear. This review discusses the roles of XBP1s in target genes transcriptional regulation. More in-depth knowledge of XBP1s target genes and transcriptional regulatory mechanisms in the future will help develop new therapeutic targets for each disease.
Highlights
endoplasmic reticulum (ER) stress is recognized by the following ER sensor proteins in mammalian cells: inositol-requiring enzyme 1 (IRE1), protein kinase R (PKR)-like ER kinase (PERK), and activating transcription factor 6 (ATF6) [9]
The dissociation of BiP from the ATF6 luminal domain induces the translocation of ATF6 to the Golgi apparatus where it undergoes proteolytic cleavage to release the N-terminal domain, which acts as a transcription factor to initiate unfolded protein response (UPR) responses [32]
XBP1s increases the transcription of genes encoding molecular chaperones and ER-associated protein degradation (ERAD) components, thereby restoring ER homeostasis
Summary
The endoplasmic reticulum (ER) plays an essential role in the synthesis, folding, assembly, and modification of transmembrane or secretory proteins [1,2]. Activating transcription factor 6; RNase, endoribonuclease; XBP1, X-box binding protein 1; ERAD, not resolved, CHOP induces apoptosis. ATF6(N) functions as an active transcription factor and upregulates target genes encoding ER chaperones, ERAD components, and XBP1. IRE1, inositol-requiring enzyme 1; PERK, protein kinase R-like ER kinase; ATF6, activating transcription factor 6; RNase, endoribonuclease; XBP1, X-box binding protein 1; ERAD, ER-associated protein degradation; eIF2α, eukaryotic translation initiation factor 2α; ATF4, activating transcription factor 4; CHOP, C/EBP homologous protein; GADD34, growth arrest and DNA damage-inducible protein 34; PP1, protein phosphatase 1; S1P, site-1 protease. The spliced Xbp mRNA is translated into the potent transcription factor XBP1s, thereby promoting the transcription of UPR-related genes encoding ER chaperones and folding enzymes This process increases the ER folding capacity. We discuss the roles of XBP1s, including the transcription of target genes, XBP1s-interacting proteins, and regulation of XBP1s activity in various types of cells
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