XBP1

X-box binding protein 1, also known as XBP1, is a is_associated_with::protein which in humans is encoded by the XBP1 is_associated_with::gene. The XBP1 gene is located on is_associated_with::chromosome 22 while a closely related is_associated_with::pseudogene has been identified and localized to chromosome 5. The XBP1 protein is a is_associated_with::transcription factor that regulates the expression of genes important to the proper functioning of the is_associated_with::immune system and in the cellular stress response.

Discovery
The X-box binding protein 1 (XBP-1) is a is_associated_with::transcription factor containing a is_associated_with::bZIP domain. It was first identified by its ability to bind to the X-box, a conserved transcriptional element in the promoter of the is_associated_with::human leukocyte antigen (HLA) DR alpha.

MHC class II gene regulation
The expression of this protein is required for the transcription of a subset of class II major histocompatibility genes. Furthermore Xbp1 heterodimerizes with other bZIP transcription factors such as is_associated_with::c-fos.

Xbp1 expression is controlled by the is_associated_with::cytokine IL-4 and the antibody is_associated_with::IGHM. Xbp1 in turn controls the expression of IL-6 which promotes plasma cell growth and of immunoglobulins in is_associated_with::B lymphocytes.

Plasma cell differentiation
XBP-1 is also essential for differentiation of is_associated_with::plasma cells (a type of antibody secreting immune cell). This differentiation requires not only the expression of XBP-1 but the expression of the spliced isoform of XBP-1s. XBP-1 regulates plasma cell differentiation independent of its known functions in the endoplasmic reticulum stress response (see below). Without normal expression of XBP-1, two important plasma cell differentiation-related genes, IRF4 and Blimp1, are misregulated, and XBP-1-lacking plasma cells fail to colonize their long-lived niches in the bone marrow and to sustain antibody secretion.

Viral replication
This protein has also been identified as a cellular transcription factor that binds to an enhancer in the promoter of the T cell leukemia virus type 1 promoter. The generation of XBP-1s during plasma cell differentiation also seems to be the cue for is_associated_with::Kaposi's sarcoma-associated is_associated_with::herpesvirus and is_associated_with::Epstein Barr virus reactivation from latency.

Endoplasmic reticulum stress response
XBP-1 is part of the is_associated_with::endoplasmic reticulum (ER) stress response, the is_associated_with::unfolded protein response (UPR). Conditions that exceed capacity of the ER provoke ER stress and trigger the unfolded protein response (UPR). As a result GRP78 is released from IRE1 to support protein folding. IRE1 oligomerises and activates its is_associated_with::ribonuclease domain through auto (self) is_associated_with::phosphorylation. Activated IRE1 catalyses the excision of a 26 nucleotide unconventional is_associated_with::intron from ubiquitously expressed XBP-1u mRNA, in a manner mechanistically similar to pre-tRNA splicing. Removal of this intron causes a frame shift in the XBP-1 coding sequence resulting in the translation of a 376 amino acid, 54 kDa, XBP-1s is_associated_with::isoform rather than the 261 amino acid, 33 kDa, XBP-1u isoform. Moreover the XBP-1u/XBP-1s ratio (XBP-1-unspliced/xbp-1-spliced ratio) correlates with the expression level of expressed proteins in order to adapt the folding capacity of the ER to the respective requirements.

Clinical significance
Abnormalities in XBP1 lead to a heightened ER stress and subsequently causes a heightened susceptibility for inflammatory processes that may contribute to is_associated_with::Alzheimer's disease. In the colon, XBP1 anomalies have been linked to is_associated_with::Crohn's disease.

A is_associated_with::single nucleotide polymorphism, C-116G, in the promoter region of XBP1 has been examined for possible association with is_associated_with::personality traits. None was found.

Interactions
XBP1 has been shown to interact with is_associated_with::estrogen receptor alpha.