Spliced or Unspliced, That Is the Question: The Biological Roles of XBP1 Isoforms in Pathophysiology

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.

An effective ER stress-related gene signature predicts overall survival and associates with tumor immunity of patients with endometrial cancer

“…When ER stress varies, XBP1-s play different roles. XBP1-s promotes cell death by altering calcium levels under strong ER Stress, while under non-fatal ER stress, XBP1-s reduces ER stress and promotes cell survival by transcriptionally regulating UPR target genes [30]. Together, it may explain the reason that XBP1 is identi ed as the protective factor in our risk signature, but expressed higher in tumor samples.…”

“…XBP1 (X-box binding protein 1) belongs to the CREB/ATF basic leucine zipper (bZIP) protein family. XBP1 can be alternatively spliced into two isoforms, the unspliced isoform (XBP1-u) is spliced into its spliced isoform (XBP1-s) under endoplasmic reticulum stress, and both isoforms are r involved in various biological pathways [30]. Berger et al screened the TCGA database and then summarized that XBP1 can be highly enriched in endometrioid endometrial tumors [31].…”

Endoplasmic reticulum stress in T cell‐mediated diseases

“…After translation, XBP1s migrates to the nucleus to regulate the transcriptional programs encoding related target genes and reduce ER stress. 50,51 IRE1α also destroys additional ER-localized mRNAs, which are at an XBP1 similar consensus site, through regulated IRE1-dependent decay (RIDD). 52,53 RIDD decreased the harmful effects of ER stress.…”

“…Once activated, IRE1α can catalyse the excision of 26‐nt introns in XBP1 mRNA to form XBP1s . After translation, XBP1s migrates to the nucleus to regulate the transcriptional programs encoding related target genes and reduce ER stress 50,51 . IRE1α also destroys additional ER‐localized mRNAs, which are at an XBP1 similar consensus site, through regulated IRE1‐dependent decay (RIDD) 52,53 .…”

Constitutive expression of spliced X-box binding protein 1 inhibits dentin formation in mice

“…Xbp1 is highly expressed in the secretory cells including odontoblasts in tooth and osteoblasts in bone as well as in exocrine glands including pancreas and salivary glands during mouse embryonic development ( Clauss et al, 1993 ). The Xbp1 gene expresses an unspliced XBP1 ( XBP1U ) mRNA that encodes a transcription factor XBP1U that is subject to rapid degradation ( Yoshida et al, 2001 ; Tirosh et al, 2006 ; Yoshida et al, 2006 ; Navon et al, 2010 ; Luo et al, 2022 ). XBP1U contains a DNA-binding domain in its amino-terminal region but does not have a transcriptional activation domain, thereby it cannot activate transcription of a gene ( Yoshida et al, 2001 ; Calfon et al, 2002 ; Tirosh et al, 2006 ; Navon et al, 2010 ; Luo et al, 2022 ).…”