XBP1

This gene encodes a transcription factor that regulates MHC class II genes by binding to a promoter element referred to as an X box. This gene product is a bZIP protein, which was also identified as a cellular transcription factor that binds to an enhancer in the promoter of the T cell leukemia virus type 1 promoter. It may increase expression of viral proteins by acting as the DNA binding partner of a viral transactivator. It has been found that upon accumulation of unfolded proteins in the endoplasmic reticulum (ER), the mRNA of this gene is processed to an active form by an unconventional splicing mechanism that is mediated by the endonuclease inositol-requiring enzyme 1 (IRE1). The resulting loss of 26 nt from the spliced mRNA causes a frame-shift and an isoform XBP1(S), which is the functionally active transcription factor. The isoform encoded by the unspliced mRNA, XBP1(U), is constitutively expressed, and thought to function as a negative feedback regulator of XBP1(S), which shuts off transcription of target genes during the recovery phase of ER stress. A pseudogene of XBP1 has been identified and localized to chromosome 5. [provided by RefSeq, Jul 2008]

X-Box Binding Protein 1

Functions as a transcription factor during endoplasmic reticulum (ER) stress by regulating the unfolded protein response (UPR). Required for cardiac myogenesis and hepatogenesis during embryonic development, and the development of secretory tissues such as exocrine pancreas and salivary gland (By similarity).
Involved in terminal differentiation of B lymphocytes to plasma cells and production of immunoglobulins (PubMed:11460154).
Modulates the cellular response to ER stress in a PIK3R-dependent manner (PubMed:20348923).
Binds to the cis-acting X box present in the promoter regions of major histocompatibility complex class II genes (PubMed:8349596).
Involved in VEGF-induced endothelial cell (EC) proliferation and retinal blood vessel formation during embryonic development but also for angiogenesis in adult tissues under ischemic conditions. Functions also as a major regulator of the UPR in obesity-induced insulin resistance and type 2 diabetes for the management of obesity and diabetes prevention (By similarity).
Isoform 1
Plays a role in the unconventional cytoplasmic splicing processing of its own mRNA triggered by the endoplasmic reticulum (ER) transmembrane endoribonuclease ERN1: upon ER stress, the emerging XBP1 polypeptide chain, as part of a mRNA-ribosome-nascent chain (R-RNC) complex, cotranslationally recruits its own unprocessed mRNA through transient docking to the ER membrane and translational pausing, therefore facilitating efficient IRE1-mediated XBP1 mRNA isoform 2 production (PubMed:19394296, PubMed:21233347).
In endothelial cells (EC), associated with KDR, promotes IRE1-mediated XBP1 mRNA isoform 2 productions in a vascular endothelial growth factor (VEGF)-dependent manner, leading to EC proliferation and angiogenesis (PubMed:23529610).
Functions as a negative feed-back regulator of the potent transcription factor XBP1 isoform 2 protein levels through proteasome-mediated degradation, thus preventing the constitutive activation of the ER stress response signaling pathway (PubMed:16461360, PubMed:25239945).
Inhibits the transactivation activity of XBP1 isoform 2 in myeloma cells (By similarity).
Acts as a weak transcriptional factor (PubMed:8657566).
Together with HDAC3, contributes to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI3K/mTORC2/Akt-dependent signaling pathway leading to EC survival under disturbed flow/oxidative stress (PubMed:25190803).
Binds to the ER stress response element (ERSE) upon ER stress (PubMed:11779464).
Binds to the consensus 5'-GATGACGTG[TG]N3[AT]T-3' sequence related to cAMP responsive element (CRE)-like sequences (PubMed:8657566).
Binds the Tax-responsive element (TRE) present in the long terminal repeat (LTR) of T-cell leukemia virus type 1 (HTLV-I) and to the TPA response elements (TRE) (PubMed:2321018, PubMed:2196176, PubMed:1903538, PubMed:8657566).
Associates preferentially to the HDAC3 gene promoter region in a static flow-dependent manner (PubMed:25190803).
Binds to the CDH5/VE-cadherin gene promoter region (PubMed:19416856).
Isoform 2
Functions as a stress-inducible potent transcriptional activator during endoplasmic reticulum (ER) stress by inducing unfolded protein response (UPR) target genes via binding to the UPR element (UPRE). Up-regulates target genes encoding ER chaperones and ER-associated degradation (ERAD) components to enhance the capacity of productive folding and degradation mechanism, respectively, in order to maintain the homeostasis of the ER under ER stress (PubMed:11779464, PubMed:25239945).
Plays a role in the production of immunoglobulins and interleukin-6 in the presence of stimuli required for plasma cell differentiation (By similarity).
Induces phospholipid biosynthesis and ER expansion (PubMed:15466483).
Contributes to the VEGF-induced endothelial cell (EC) growth and proliferation in a Akt/GSK-dependent and/or -independent signaling pathway, respectively, leading to beta-catenin nuclear translocation and E2F2 gene expression (PubMed:23529610).
Promotes umbilical vein EC apoptosis and atherosclerotisis development in a caspase-dependent signaling pathway, and contributes to VEGF-induced EC proliferation and angiogenesis in adult tissues under ischemic conditions (PubMed:19416856, PubMed:23529610).
Involved in the regulation of endostatin-induced autophagy in EC through BECN1 transcriptional activation (PubMed:23184933).
Plays a role as an oncogene by promoting tumor progression: stimulates zinc finger protein SNAI1 transcription to induce epithelial-to-mesenchymal (EMT) transition, cell migration and invasion of breast cancer cells (PubMed:25280941).
Involved in adipocyte differentiation by regulating lipogenic gene expression during lactation. Plays a role in the survival of both dopaminergic neurons of the substantia nigra pars compacta (SNpc), by maintaining protein homeostasis and of myeloma cells. Increases insulin sensitivity in the liver as a response to a high carbohydrate diet, resulting in improved glucose tolerance. Improves also glucose homeostasis in an ER stress- and/or insulin-independent manner through both binding and proteasome-induced degradation of the transcription factor FOXO1, hence resulting in suppression of gluconeogenic genes expression and in a reduction of blood glucose levels. Controls the induction of de novo fatty acid synthesis in hepatocytes by regulating the expression of a subset of lipogenic genes in an ER stress- and UPR-independent manner (By similarity).
Associates preferentially to the HDAC3 gene promoter region in a disturbed flow-dependent manner (PubMed:25190803).
Binds to the BECN1 gene promoter region (PubMed:23184933).
Binds to the CDH5/VE-cadherin gene promoter region (PubMed:19416856).
Binds to the ER stress response element (ERSE) upon ER stress (PubMed:11779464).
Binds to the 5'-CCACG-3' motif in the PPARG promoter (By similarity).

Biological Process adipose tissue development Source:UniProtKB
Biological Process angiogenesis Source:UniProtKB
Biological Process apoptotic process Source:UniProtKB-KW
Biological Process ATF6-mediated unfolded protein response Source:ComplexPortal1 Publication
Biological Process autophagy Source:UniProtKB-KW
Biological Process cellular response to amino acid stimulus Source:UniProtKB
Biological Process cellular response to fluid shear stress Source:UniProtKB
Biological Process cellular response to fructose stimulus Source:UniProtKB
Biological Process cellular response to glucose starvation Source:UniProtKB
Biological Process cellular response to glucose stimulus Source:UniProtKB
Biological Process cellular response to insulin stimulus Source:UniProtKB
Biological Process cellular response to interleukin-4 Source:UniProtKB
Biological Process cellular response to laminar fluid shear stress Source:UniProtKB
Biological Process cellular response to lipopolysaccharide Source:UniProtKB1 Publication
Biological Process cellular response to nutrient Source:UniProtKB
Biological Process cellular response to oxidative stress Source:UniProtKB
Biological Process cellular response to peptide hormone stimulus Source:UniProtKB
Biological Process cellular response to vascular endothelial growth factor stimulus Source:UniProtKB
Biological Process cellular triglyceride homeostasis Source:UniProtKB
Biological Process cholesterol homeostasis Source:UniProtKB
Biological Process endoplasmic reticulum unfolded protein response Source:UniProtKB
Biological Process endothelial cell proliferation Source:UniProtKB
Biological Process ERAD pathway Source:ComplexPortal1 Publication
Biological Process fatty acid biosynthetic process Source:ParkinsonsUK-UCL1 Publication
Biological Process fatty acid homeostasis Source:UniProtKB
Biological Process immune response Source:ParkinsonsUK-UCL1 Publication
Biological Process IRE1-mediated unfolded protein response Source:ParkinsonsUK-UCL2 Publications
Biological Process liver development Source:UniProtKB
Biological Process muscle organ development Source:UniProtKB-KW
Biological Process negative regulation of apoptotic process Source:UniProtKB
Biological Process negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway Source:ParkinsonsUK-UCL1 Publication
Biological Process negative regulation of endoplasmic reticulum unfolded protein response Source:UniProtKB
Biological Process negative regulation of ERK1 and ERK2 cascade Source:BHF-UCL
Biological Process negative regulation of myotube differentiation Source:UniProtKB
Biological Process negative regulation of pathway-restricted SMAD protein phosphorylation Source:BHF-UCL
Biological Process negative regulation of transcription by RNA polymerase II Source:UniProtKB
Biological Process negative regulation of transforming growth factor beta receptor signaling pathway Source:BHF-UCL
Biological Process neuron development Source:UniProtKB
Biological Process organelle organization Source:ParkinsonsUK-UCL
Biological Process phosphatidylinositol 3-kinase signaling Source:UniProtKB
Biological Process positive regulation of angiogenesis Source:BHF-UCL1 Publication
Biological Process positive regulation of autophagy Source:UniProtKB
Biological Process positive regulation of B cell differentiation Source:UniProtKB1 Publication
Biological Process positive regulation of cell migration Source:BHF-UCL1 Publication
Biological Process positive regulation of cell population proliferation Source:BHF-UCL1 Publication
Biological Process positive regulation of endoplasmic reticulum unfolded protein response Source:UniProtKB1 Publication
Biological Process positive regulation of endothelial cell apoptotic process Source:UniProtKB
Biological Process positive regulation of ER-associated ubiquitin-dependent protein catabolic process Source:ParkinsonsUK-UCL
Biological Process positive regulation of fat cell differentiation Source:UniProtKB
Biological Process positive regulation of hepatocyte proliferation Source:UniProtKB
Biological Process positive regulation of histone methylation Source:UniProtKB
Biological Process positive regulation of immunoglobulin production Source:UniProtKB1 Publication
Biological Process positive regulation of interleukin-6 production Source:UniProtKB
Biological Process positive regulation of lactation Source:UniProtKB
Biological Process positive regulation of MHC class II biosynthetic process Source:UniProtKB1 Publication
Biological Process positive regulation of phospholipid biosynthetic process Source:BHF-UCL
Biological Process positive regulation of plasma cell differentiation Source:UniProtKB1 Publication
Biological Process positive regulation of protein acetylation Source:UniProtKB
Biological Process positive regulation of protein import into nucleus Source:UniProtKB
Biological Process positive regulation of protein kinase B signaling Source:BHF-UCL
Biological Process positive regulation of protein phosphorylation Source:BHF-UCL
Biological Process positive regulation of T cell differentiation Source:UniProtKB1 Publication
Biological Process positive regulation of TOR signaling Source:UniProtKB
Biological Process positive regulation of transcription by RNA polymerase II Source:ParkinsonsUK-UCL1 Publication
Biological Process positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress Source:ParkinsonsUK-UCL
Biological Process positive regulation of transcription from RNA polymerase II promoter involved in unfolded protein response Source:UniProtKB
Biological Process positive regulation of vascular associated smooth muscle cell migration Source:BHF-UCL
Biological Process positive regulation of vascular associated smooth muscle cell proliferation Source:BHF-UCL
Biological Process positive regulation of vascular wound healing Source:BHF-UCL1 Publication
Biological Process protein destabilization Source:UniProtKB
Biological Process protein transport Source:UniProtKB-KW
Biological Process regulation of cell growth Source:UniProtKB
Biological Process regulation of protein stability Source:UniProtKB
Biological Process regulation of transcription by RNA polymerase II Source:ComplexPortal1 Publication
Biological Process response to endoplasmic reticulum stress Source:UniProtKB
Biological Process response to insulin-like growth factor stimulus Source:UniProtKB
Biological Process sterol homeostasis Source:UniProtKB
Biological Process transcription by RNA polymerase II Source:UniProtKB
Biological Process ubiquitin-dependent protein catabolic process Source:UniProtKB
Biological Process vascular endothelial growth factor receptor signaling pathway Source:UniProtKB

Endoplasmic reticulum
Colocalizes with ERN1 and KDR in the endoplasmic reticulum in endothelial cells in a vascular endothelial growth factor (VEGF)-dependent manner (PubMed:23529610).
Isoform 1
Nucleus
Cytoplasm
Endoplasmic reticulum membrane
Endoplasmic reticulum membrane
Membrane
Shows no preferential localization to either the nucleus or the cytoplasm (By similarity).
Shuttles between the nucleus and the cytoplasm in a CRM1-dependent manner (PubMed:16461360).
Localizes predominantly at the endoplasmic reticulum membrane as a membrane-spanning protein; whereas may be only marginally localized on the cytosolic side of the ER membrane as a peripheral membrane (PubMed:19394296, PubMed:25190803).
Isoform 2
Nucleus
Cytoplasm
Localizes predominantly in the nucleus. Colocalizes in the nucleus with SIRT1. Translocates into the nucleus in a PIK3R-, ER stress-induced- and/or insulin-dependent manner (By similarity).
X-box-binding protein 1, cytoplasmic form
Cytoplasm
Nucleus
Localizes in the cytoplasm and nucleus after HM13/SPP-mediated intramembranaire proteolytic cleavage of isoform 1 (PubMed:25239945).

Major affective disorder 7 (MAFD7):
A major psychiatric disorder that is characterized by severe mood swings, with fluctuation between two abnormal mood states (manic or major depressive episode). Mania is accompanied by symptoms of euphoria, irritability, or excitation, whereas depression is associated with low mood and decreased motivation and energy.

Cytoplasmic: 1-185
Helical: 186-203
Lumenal: 204-261

Isoform 2
Acetylated by EP300; acetylation positively regulates the transcriptional activity of XBP1 isoform 2 (PubMed:20955178).
Isoform 2 is deacetylated by SIRT1; deacetylation negatively regulates the transcriptional activity of XBP1 isoform 2 (PubMed:20955178).
Isoform 1
Ubiquitinated, leading to proteasome-mediated degradation in response to ER stress (PubMed:11779464, PubMed:16461360, PubMed:25239945).
X-box-binding protein 1, cytoplasmic form and luminal form are produced by intramembrane proteolytic cleavage of ER membrane-anchored isoform 1 triggered by HM13/SPP in a DERL1-RNF139-dependent and VCP/p97-independent manner. X-box-binding protein 1, luminal form is ubiquitinated leading to proteasomal degradation (PubMed:25239945).