Disease relevance of Xbp1

• When cells were infected with a recombinant adenovirus (AdV) encoding dominant-negative XBP1 (AdV-XBP1dn), UPR markers were reduced; however, hypoxia/reoxygenation-induced apoptosis increased [1].
• Mouse hepatitis virus infection activates the Ire1/XBP1 pathway of the unfolded protein response [2].
• XBP-1 is a CREB/ATF family transcription factor highly expressed in hepatocellular carcinomas [3].
• In this report, we have examined the role of IRE1-alpha and XBP1 in activation of the hepatitis B virus S promoter by ER stress [4].
• An infection of human foreskin fibroblasts with human cytomegalovirus induced XBP-1 splicing in a manner that coincides with US11 expression [5].

High impact information on Xbp1

• Mammalian XBP-1 is essential for immunoglobulin secretion and development of plasma cells, and high levels of XBP-1 messenger RNA are found in specialized secretory cells [6].
• IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA [6].
• Mouse lymphoid chimaeras deficient in XBP-1 possessed normal numbers of activated B lymphocytes that proliferated, secreted cytokines and formed normal germinal centres [7].
• XBP-1 transcripts were rapidly upregulated in vitro by stimuli that induce plasma-cell differentiation, and were found at high levels in plasma cells from rheumatoid synovium [7].
• Furthermore, the absence of a specific X box binding protein in patients with severe combined immunodeficiency disease whose cells lack class II suggests an important role for these proteins in class II regulation [8].

Biological context of Xbp1

• By gene expression profiling, we defined a set of genes whose induction during mouse plasmacytic differentiation is dependent on Blimp-1 and/or XBP1 [9].
• Thus, XBP1 coordinates diverse changes in cellular structure and function resulting in the characteristic phenotype of professional secretory cells [9].
• In addition, XBP1 increased cell size, lysosome content, mitochondrial mass and function, ribosome numbers, and total protein synthesis [9].
• XBP1 induces certain ER-targeted proteins, eg, glucose-regulated protein 78 (GRP78), that help resolve the ER stress and foster cell survival [1].
• Mice lacking XBP-1 displayed hypoplastic fetal livers, whose reduced hematopoiesis resulted in death from anemia [3].

Anatomical context of Xbp1

• Differentiating xbp1-deficient B cells induced Blimp-1 normally but failed to upregulate genes encoding many secretory pathway components [9].
• XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation [9].
• Conversely, ectopic expression of XBP1 induced a wide spectrum of secretory pathway genes and physically expanded the endoplasmic reticulum [9].
• Therefore, XBP-1 is a transcription factor essential for hepatocyte growth [3].
• XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands [10].

Associations of Xbp1 with chemical compounds

• XBP-1(-/-) and XBP-1(+/+) primary B cells synthesize IgM at comparable levels at the onset of stimulation with lipopolysaccharide or CpG [11].
• Here, we report that enforced expression of XBP1(S), the active form of the XBP1 transcription factor generated by UPR-mediated splicing of XBP1 mRNA, is sufficient to induce synthesis of phosphatidylcholine, the primary phospholipid of the ER membrane [12].
• Three factors that positively regulate CHOP expression (ATF6, ATF4 and XBP-1) were activated and/or induced by indomethacin [13].
• Unexpectedly, we found that one of the mutants activates transcription of both Xbp-1-specific and non-Xbp-1-dependent UPR targets in response to tunicamycin treatment, even more potently than does wild type Xbp-1 [14].
• X-box-binding protein 1 (XBP-1) is a basic-region leucine zipper protein in the cyclic AMP response element binding protein/activating transcription factor (CREB/ATF) family of transcription factors involved in different cell-differentiation processes [15].

Regulatory relationships of Xbp1

• The isolated neurite culture system and time-lapse imaging demonstrated that Xbp1 was activated in neurites in response to brain-derived neurotrophic factor (BDNF), followed by subsequent translocation of the active Xbp1 into the nucleus [16].

Other interactions of Xbp1

• Signals involved in plasma cell differentiation, specifically interleukin-4, control the transcription of XBP-1, whereas its post-transcriptional processing is dependent on synthesis of immunoglobulins during B cell differentiation [17].
• We also show that XBP-1 is involved in controlling the production of interleukin-6, a cytokine that is essential for plasma cell survival [17].
• Contrary to expectation, degradation of proteins from the ER, using TCRalpha or US11-mediated degradation of class I major histocompatibility complex molecules as substrates, is normal in XBP-1(-/-) B cells [11].

Analytical, diagnostic and therapeutic context of Xbp1

• Changes in levels of processed X-box protein 1 (xbp1), glucose-regulated protein 78 (grp78), growth arrest and DNA damage-inducible gene 153 (gadd153) and heat-shock protein 70 (hsp70) mRNA, indicating impaired endoplasmic reticulum (ER) and cytoplasmic functioning, were evaluated by quantitative PCR [18].
• To study the function(s) of TREB5 in normal development, we have generated TREB5 deficient mice by gene targeting [19].
• Southern blot analysis of the mouse genomic DNA demonstrated that positive bands exactly coincide with those expected from sequences of the cloned genes, indicating that the mouse TREB5 gene is present as a single copy [20].
• A marked increase in processed xbp1 mRNA levels during reperfusion was observed, most pronounced (about 35-fold) after 1-h occlusion of the right middle cerebral artery [21].
• Detection of XBP-1 by immunofluorescence at days 0 (control culture without AA and BGP), 8 and 21 showed that the protein has a major cytoplasmic perinuclear location [15].

References