Function
XBP1 (X-box binding protein 1) functions as a transcription factor during endoplasmic reticulum (ER) stress by regulating the unfolded protein response (UPR). It is essential for cardiac myogenesis and hepatogenesis during embryonic development, as well as the development of secretory tissues such as the exocrine pancreas and salivary gland. XBP1 is also involved in the terminal differentiation of B lymphocytes into plasma cells and the production of immunoglobulins. It modulates the cellular response to ER stress in a PIK3R-dependent manner. XBP1 binds to the cis-acting X box present in the promoter regions of major histocompatibility complex class II genes. It participates in VEGF-induced endothelial cell (EC) proliferation and retinal blood vessel formation during embryonic development, and also contributes to angiogenesis in adult tissues under ischemic conditions.
XBP1 acts as a major regulator of the UPR in obesity-induced insulin resistance and type 2 diabetes, playing a role in the management of obesity and diabetes prevention. It also participates in the unconventional cytoplasmic splicing processing of its own mRNA, triggered by the endoplasmic reticulum (ER) transmembrane endoribonuclease ENR1. 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, facilitating efficient IRE1-mediated XBP1 mRNA isoform 2 production. In endothelial cells (EC), associated with KDR, it promotes IRE1-mediated XBP1 mRNA isoform 2 production in a vascular endothelial growth factor (VEGF)-dependent manner, leading to EC proliferation and angiogenesis. XBP1 functions as a negative feedback 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. It inhibits the transactivation activity of XBP1 isoform 2 in myeloma cells and acts as a weak transcriptional factor.
Together with HDAC3, XBP1 contributes to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway, leading to EC survival under disturbed flow/oxidative stress. XBP1 binds to the ER stress response element (ERSE) upon ER stress and to the consensus 5'-GATGACGTG. It 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). XBP1 up-regulates target genes encoding ER chaperones and ER-associated degradation (ERAD) components to enhance the capacity of productive folding and degradation mechanisms, respectively, in order to maintain the homeostasis of the ER under ER stress. It plays a role in the production of immunoglobulins and interleukin-6 in the presence of stimuli required for plasma cell differentiation. XBP1 induces phospholipid biosynthesis and ER expansion.
It contributes to VEGF-induced endothelial cell (EC) growth and proliferation in an Akt/GSK-dependent and/or -independent signaling pathway, respectively, leading to beta-catenin nuclear translocation and E2F2 gene expression. XBP1 promotes umbilical vein EC apoptosis and atherosclerosis development in a caspase-dependent signaling pathway, and contributes to VEGF-induced EC proliferation and angiogenesis in adult tissues under ischemic conditions. It is involved in the regulation of endostatin-induced autophagy in EC through BECN1 transcriptional activation. XBP1 acts as an oncogene by promoting tumor progression: it stimulates zinc finger protein SNAI1 transcription to induce epithelial-to-mesenchymal (EMT) transition, cell migration and invasion of breast cancer cells. It participates in adipocyte differentiation by regulating lipogenic gene expression during lactation. XBP1 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.
XBP1 increases insulin sensitivity in the liver as a response to a high carbohydrate diet, resulting in improved glucose tolerance. It also improves 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 a reduction of blood glucose levels. XBP1 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. It associates preferentially to the HDAC3 gene promoter region in a disturbed flow-dependent manner. XBP1 binds to the BECN1 gene promoter region, the CDH5/VE-cadherin gene promoter region, the ER stress response element (ERSE) upon ER stress, and the 5'-CCACG-3' motif in the PPARG promoter.