XBP1

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

Discovery

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

Function

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 c-fos.

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

Plasma cell differentiation

XBP-1 is also essential for differentiation of 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 Kaposi's sarcoma-associated herpesvirus and Epstein Barr virus reactivation from latency.

Endoplasmic reticulum stress response

XBP-1 is upregulated as part of the endoplasmic reticulum (ER) stress response, the unfolded protein response (UPR). This increase in transcription requires an ER stress response consensus binding element in the promoter. XBP-1u is ubiquitously expressed but under conditions of ER-stress, the XBP-1u mRNA is processed by IRE1. Activated IRE1 oligomerises and activates its ribonuclease domain through auto (self) phosphorylation. Because the lumen of the ER is continuous with the perinuclear space, the activated ribonuclease domains can penetrate the inner leaflet of the nuclear envelope. Within the nucleus, activated IRE1 catalyses the excision of a 26 nucleotide unconventional intron from XBP-1 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 371 amino acid, 54 kDa, XBP-1s isoform rather than the 261 amino acid, 33 kDa, XBP-1u isoform.

Clinical signficance

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

Abnormalities in XBP1 lead to a heightened ER stress and subsequently causes a heightened susceptibility for inflammatory processes.

Specifically in the colon, XBP1 anomalies have been linked to Crohn's disease.

Interactions

XBP1 has been shown to interact with Estrogen receptor alpha.