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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

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

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. The ''XBP1'' gene is located on

chromosome 22 Chromosome 22 is one of the 23 pairs of chromosomes in human cells. Humans normally have two copies of chromosome 22 in each cell. Chromosome 22 is the second smallest human chromosome, spanning about 49 million DNA base pairs and representing ...

while a closely related

pseudogene Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Most arise as superfluous copies of functional genes, either directly by DNA duplication or indirectly by reverse transcription of an mRNA transcript. Pseudogenes ar ...

has been identified and localized to

chromosome 5 Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 181 million base pairs (the building blocks of DNA) and represents almost 6% of the total DNA in cells. Ch ...

. 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 of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

that regulates the

expression Expression may refer to: Linguistics * Expression (linguistics), a word, phrase, or sentence * Fixed expression, a form of words with a specific meaning * Idiom, a type of fixed expression * Metaphorical expression, a particular word, phrase, o ...

of genes important to the proper functioning of the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...

and in the cellular stress response.

Discovery

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

containing a

bZIP domain The Basic Leucine Zipper Domain (bZIP domain) is found in many DNA binding eukaryotic proteins. One part of the domain contains a region that mediates sequence specific DNA binding properties and the leucine zipper that is required to hold tog ...

. 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 or complex is a complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for the regulation of the immune system. The HLA system is also known as the human version of th ...

(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 Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the ''FOS'' gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV (Finkel–Biskis–Jink ...

. 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 peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...

IL-4 and the antibody IGHM. XBP1 in turn controls the expression of IL-6 which promotes plasma cell growth and of

immunoglobulins An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

B lymphocyte B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

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 lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific subs ...

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 Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...

differentiation. Eosinophils lacking XBP1 exhibit defects in granule proteins.

Angiogenesis

XBP1 acts to regulate endothelial cell proliferation through growth factor pathways, leading to

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splittin ...

. Additionally, XBP1 protects endothelial cells from oxidative stress by interacting with

HDAC3 Histone deacetylase 3 is an enzyme encoded by the ''HDAC3'' gene in both humans and mice. Function Histones are highly alkaline proteins that package and order DNA into structural units called nucleosomes, which comprise the major protein comp ...

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-associated

herpesvirus ''Herpesviridae'' is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word ''ἕρπειν ...

and Epstein Barr virus reactivation from latency.

Endoplasmic reticulum stress response

XBP1 is part of the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...

(ER) stress response, the

unfolded protein response The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between all mammalian species, as well as yeast and worm organisms. The UPR is activated in resp ...

(UPR). Conditions that exceed capacity of the ER provoke ER stress and trigger the unfolded protein response (UPR). As a result,

GRP78 Binding immunoglobulin protein (BiP) also known as 78 kDa glucose-regulated protein (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) is a protein that in humans is encoded by the ''HSPA5'' gene. BiP is a HSP70 molecular chaperone located in the l ...

is released from IRE1 to support protein folding. IRE1 oligomerises and activates its

ribonuclease Ribonuclease (commonly abbreviated RNase) is a type of nuclease that catalyzes the degradation of RNA into smaller components. Ribonucleases can be divided into endoribonucleases and exoribonucleases, and comprise several sub-classes within the ...

domain through auto (self)

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

. Activated IRE1 catalyses the excision of a 26 nucleotide unconventional

intron An intron is any Nucleic acid sequence, 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 ...

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 A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some is ...

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 that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...

. 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 (which may be bloody if inflammation is severe), fever, abdominal distensi ...

. A

single nucleotide polymorphism In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...

, C116G, in the promoter region of ''XBP1'' has been examined for possible associations with

personality trait In psychology, trait theory (also called dispositional theory) is an approach to the study of human personality. Trait theorists are primarily interested in the measurement of ''traits'', which can be defined as habitual patterns of behaviour, tho ...

s. None were found.

Interactions

XBP1 has been shown to

interact Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...

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

{{Transcription factors, g1