XBP1
Encyclopedia
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.
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
.
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.
of plasma cell
s (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.
-associated herpesvirus and Epstein Barr virus reactivation from latency.
(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.
, 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, like in Alzheimer's disease
.
Specifically in the colon
, XBP1 anomalies have been linked to Crohn's disease
.
with Estrogen receptor alpha
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
which in humans is encoded by the XBP1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. The XBP1 gene is located on chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
22 while a closely related pseudogene
Pseudogene
Pseudogenes are dysfunctional relatives of known genes that have lost their protein-coding ability or are otherwise no longer expressed in the cell...
has been identified and localized to chromosome 5. The XBP1 protein is a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
that regulates the expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of genes important to the proper functioning of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
and in the cellular stress response.
Discovery
The X-box binding protein 1 (XBP-1) is a transcription factorTranscription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
containing a bZIP domain
BZIP domain
The Basic Leucine Zipper 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 for the dimerization of two DNA binding regions. The DNA binding region...
. 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
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
(HLA) DR alpha
HLA-DRA
HLA class II histocompatibility antigen, DR alpha chain is a protein that in humans is encoded by the HLA-DRA gene. HLA-DRA encodes the alpha subunit of HLA-DR. Unlike the alpha chains of other Human MHC class II molecules, the alpha subunit is practically invariable...
.
MHC class II gene regulation
The expression of this protein is required for the transcription of a subset of class II major histocompatibilityMHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....
genes. Furthermore Xbp1 heterodimerizes with other bZIP transcription factors such as c-fos
C-Fos
In the field of molecular biology and Genetics, c-Fos is a protein encoded by the FOS gene.-Structure and function:c-Fos is a cellular proto-oncogene belonging to the immediate early gene family of transcription factors. c-Fos has a leucine-zipper DNA binding domain, and a transactivation domain at...
.
Xbp1 expression is controlled by the cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
IL-4
Interleukin 4
Interleukin-4, abbreviated IL-4, is a cytokine that induces differentiation of naive helper T cells to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4. The cell that initially produces IL-4, thus inducing Th0 differentiation, has not been identified, but recent...
and the antibody IGHM
IGHM
Ig mu chain C region is a protein that in humans is encoded by the IGHM gene.It is associated with agammaglobulinemia-1.-Further reading:...
. Xbp1 in turn controls the expression of IL-6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
which promotes plasma cell growth and of immunoglobulins
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
in B lymphocytes.
Plasma cell differentiation
XBP-1 is also essential for differentiationCellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
of plasma cell
Plasma cell
Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...
s (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 sarcomaKaposi's sarcoma
Kaposi's sarcoma is a tumor caused by Human herpesvirus 8 , also known as Kaposi's sarcoma-associated herpesvirus . It was originally described by Moritz Kaposi , a Hungarian dermatologist practicing at the University of Vienna in 1872. It became more widely known as one of the AIDS defining...
-associated herpesvirus and Epstein Barr virus reactivation from latency.
Endoplasmic reticulum stress response
XBP-1 is upregulated as part of the endoplasmic reticulumEndoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
(ER) stress response, the unfolded protein response
Unfolded protein response
The unfolded protein response is a cellular stress response related to the endoplasmic reticulum. It is a stress response that has been found to be conserved between all mammalian species, as well as yeast and worm organisms...
(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
ERN1
Serine/threonine-protein kinase/endoribonuclease IRE1 is an enzyme that in humans is encoded by the ERN1 gene.-Interactions:ERN1 has been shown to interact with Heat shock protein 90kDa alpha , member A1.-Further reading:...
. Activated IRE1 oligomerises and activates its ribonuclease
Ribonuclease
Ribonuclease 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 EC 2.7 and 3.1 classes of enzymes.-Function:All organisms studied contain...
domain through auto (self) phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
. Because the lumen of the ER is continuous with the perinuclear space, the activated ribonuclease
Ribonuclease
Ribonuclease 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 EC 2.7 and 3.1 classes of enzymes.-Function:All organisms studied contain...
domains can penetrate the inner leaflet of the nuclear envelope. Within the nucleus, activated IRE1 catalyses the excision of a 26 nucleotide unconventional intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
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 polymorphismSingle nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
, 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, like in Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
Specifically in the colon
Colon (anatomy)
The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
, XBP1 anomalies have been linked to Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
.
Interactions
XBP1 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Estrogen receptor alpha
Estrogen receptor alpha
Estrogen receptor alpha , also known as NR3A1 , is a nuclear receptor that is activated by the sex hormone estrogen...
.