X-box binding protein 1, also known as XBP1, is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

which in humans is encoded by the ''XBP1''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. The ''XBP1'' gene is located on chromosome 22 while a closely related

pseudogene Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Pseudogenes can be formed from both protein-coding genes and non-coding genes. In the case of protein-coding genes, most pseudogenes arise as superfluous copies of fun ...

has been identified and localized to chromosome 5. The XBP1 protein is a

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...

that regulates the expression of genes important to the proper functioning of the

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

and in the cellular stress response.

Discovery

The X-box binding protein 1 (XBP1) is a

containing a bZIP domain. It was first identified by its ability to bind to the Xbox, a conserved transcriptional element in the promoter of the

human leukocyte antigen The human leukocyte antigen (HLA) system is a complex of genes on chromosome 6 in humans that encode cell-surface proteins responsible for regulation of the immune system. The HLA system is also known as the human version of the major histo ...

(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 Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

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

XBP1 is also essential for differentiation of

plasma cell Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances ca ...

s (a type of antibody secreting immune cell). This differentiation requires not only the expression of XBP1 but the expression of the spliced isoform of XBP1s. XBP1 regulates plasma cell differentiation independent of its known functions in the endoplasmic reticulum stress response (see below). Without normal expression of XBP1, two important plasma cell differentiation-related genes, IRF4 and Blimp1, are misregulated, and XBP1-lacking plasma cells fail to colonize their long-lived niches in the bone marrow and to sustain antibody secretion.

Eosinophil differentiation

XBP1 is required for eosinophil differentiation. Eosinophils lacking XBP1 exhibit defects in granule proteins.

Angiogenesis

XBP1 acts to regulate endothelial cell proliferation through growth factor pathways, leading to angiogenesis. Additionally, XBP1 protects endothelial cells from oxidative stress by interacting with HDAC3.

Viral replication

This protein has also been identified as a cellular transcription factor that binds to an enhancer in the promoter of the Human T-lymphotropic virus 1. The generation of XBP1s during plasma cell differentiation also seems to be the cue for

Kaposi's sarcoma Kaposi's sarcoma (KS) is a type of cancer that can form masses on the skin, in lymph nodes, in the mouth, or in other organs. The skin lesions are usually painless, purple and may be flat or raised. Lesions can occur singly, multiply in a limite ...

-associated herpesvirus and Epstein Barr virus reactivation from latency.

Endoplasmic reticulum stress response

XBP1 is part of the

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

(ER) stress response and the 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 ribonuclease domain through auto (self)

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

. Activated IRE1 catalyses the excision of a 26 nucleotide unconventional

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of the cistron .e., gen ...

from ubiquitously expressed XBP1u mRNA, in a manner mechanistically similar to pre-tRNA splicing. Removal of this intron causes a frame shift in the XBP1 coding sequence resulting in the translation of a 376 amino acid, 40 kDa, XBP-1s isoform rather than the 261 amino acid, 33 kDa, XBP1u isoform. Moreover, the XBP1u/XBP1s ratio (XBP1-unspliced/XBP1-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

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. In the colon, XBP1 anomalies have been linked to

Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the ...

. A single nucleotide polymorphism, C116G, in the promoter region of ''XBP1'' has been examined for possible associations with personality traits. None were found.

Interactions

XBP1 has been shown to interact with

estrogen receptor alpha Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein) that is activated by the sex ...

References

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