XBP1

X-box binding protein 1
Identifiers
Symbols	XBP1 ; TREB-5; TREB5; XBP-1; XBP2
External IDs	OMIM: 194355 MGI: 98970 HomoloGene: 3722 ChEMBL: 1741176 GeneCards: XBP1 Gene
Gene ontology Molecular function • RNA polymerase II regulatory region sequence-specific DNA binding • RNA polymerase II transcription factor activity, sequence-specific DNA binding • core promoter binding • RNA polymerase II transcription factor binding • enhancer sequence-specific DNA binding • protease binding • DNA binding • transcription factor activity, sequence-specific DNA binding • protein binding • protein kinase binding • estrogen receptor binding • chromatin DNA binding • ubiquitin protein ligase binding • phosphatidylinositol 3-kinase regulatory subunit binding • protein homodimerization activity • histone deacetylase binding • transcription regulatory region DNA binding • protein heterodimerization activity Cellular component • nucleus • nucleoplasm • cytoplasm • endoplasmic reticulum • endoplasmic reticulum membrane • cytosol • integral component of membrane • integral component of endoplasmic reticulum membrane Biological process • negative regulation of transcription from RNA polymerase II promoter • angiogenesis • liver development • positive regulation of protein phosphorylation • endothelial cell proliferation • positive regulation of immunoglobulin production • transcription from RNA polymerase II promoter • ubiquitin-dependent protein catabolic process • fatty acid biosynthetic process • autophagy • immune response • positive regulation of transcription from RNA polymerase II promoter involved in unfolded protein response • organelle organization • muscle organ development • regulation of autophagy • positive regulation of autophagy • negative regulation of myotube differentiation • phosphatidylinositol 3-kinase signaling • protein transport • cell growth • endoplasmic reticulum unfolded protein response • exocrine pancreas development • positive regulation of histone methylation • regulation of protein stability • protein destabilization • cellular response to nutrient • positive regulation of TOR signaling • cellular response to insulin stimulus • cellular response to oxidative stress • response to endoplasmic reticulum stress • cellular triglyceride homeostasis • cellular response to vascular endothelial growth factor stimulus • IRE1-mediated unfolded protein response • ATF6-mediated unfolded protein response • cellular response to glucose starvation • response to drug • cholesterol homeostasis • positive regulation of transcription factor import into nucleus • negative regulation of apoptotic process • cellular protein metabolic process • positive regulation of MHC class II biosynthetic process • positive regulation of B cell differentiation • positive regulation of T cell differentiation • positive regulation of fat cell differentiation • positive regulation of transcription from RNA polymerase II promoter • vascular endothelial growth factor receptor signaling pathway • neuron development • positive regulation of immunoglobulin secretion • response to electrical stimulus • fatty acid homeostasis • sterol homeostasis • serotonin secretion, neurotransmission • adipose tissue development • epithelial cell maturation involved in salivary gland development • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress • cellular response to lipopolysaccharide • cellular response to amino acid stimulus • cellular response to antibiotic • cellular response to fructose stimulus • cellular response to glucose stimulus • cellular response to interleukin-4 • cellular response to peptide hormone stimulus • cellular response to fluid shear stress • cellular response to laminar fluid shear stress • positive regulation of plasma cell differentiation • negative regulation of endoplasmic reticulum unfolded protein response • positive regulation of endoplasmic reticulum unfolded protein response • positive regulation of phospholipid biosynthetic process by positive regulation of transcription from RNA polymerase II promoter • positive regulation of proteasomal protein catabolic process • positive regulation of protein acetylation • negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway • positive regulation of ER-associated ubiquitin-dependent protein catabolic process • positive regulation of lactation • response to insulin-like growth factor stimulus • positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress • positive regulation of hepatocyte proliferation • positive regulation of endothelial cell apoptotic process • positive regulation of interleukin-6 secretion Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7494	22433
Ensembl	ENSG00000100219	ENSMUSG00000020484
UniProt	P17861	O35426
RefSeq (mRNA)	NM_001079539	NM_001271730
RefSeq (protein)	NP_001073007	NP_001258659
Location (UCSC)	Chr 22: 28.79 – 28.8 Mb	Chr 11: 5.52 – 5.53 Mb
PubMed search

X-box binding protein 1, also known as XBP1, is a protein which in humans is encoded by the XBP1 gene.^[1][2] The XBP1 gene is located on chromosome 22 while a closely related pseudogene has been identified and localized to chromosome 5.^[3] 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.^[4]

Discovery

The X-box binding protein 1 (XBP1) is a transcription factor 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 (HLA) DR alpha.^[2]

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.^[5] Furthermore, XBP1 heterodimerizes with other bZIP transcription factors such as c-fos.^[5]

XBP1 expression is controlled by the cytokine IL-4 and the antibody IGHM.^[6] XBP1 in turn controls the expression of IL-6 which promotes plasma cell growth and of immunoglobulins in B lymphocytes.^[6]

Plasma cell differentiation

XBP1 is also essential for differentiation of plasma cells (a type of antibody secreting immune cell).^[6] 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).^[7] 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.^[7]

Eosinophil differentiation

XBP1 is required for eosinophil differentiation. Eosinophils lacking XBP1 exhibit defects in granule proteins.^[8]

Angiogenesis

XBP1 acts to regulate endothelial cell proliferation through growth factor pathways,^[9] leading to angiogenesis. Additionally, XBP1 protects endothelial cells from oxidative stress by interacting with HDAC3.^[10]

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 XBP1s 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

XBP1 is part of the endoplasmic reticulum (ER) stress response, the unfolded protein response (UPR).^[6] 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.^[11] IRE1 oligomerises and activates its ribonuclease domain through auto (self) phosphorylation. Activated IRE1 catalyses the excision of a 26 nucleotide unconventional intron 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, 54 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.^[12]

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.^[13] In the colon, XBP1 anomalies have been linked to Crohn's disease.^[14]

A single nucleotide polymorphism, C-116G, in the promoter region of XBP1 has been examined for possible associations with personality traits. None were found.^[15]

Interactions

XBP1 has been shown to interact with estrogen receptor alpha.^[16]

See also

• Unfolded protein response

References

1. "Entrez Gene: XBP1 X-box binding protein 1".
2. Liou HC, Boothby MR, Finn PW, Davidon R, Nabavi N, Zeleznik-Le NJ, Ting JP, Glimcher LH (March 1990). "A new member of the leucine zipper class of proteins that binds to the HLA DR alpha promoter". Science 247 (4950): 1581–4. doi:10.1126/science.2321018. PMID 2321018.
3. Liou HC, Eddy R, Shows T, Lisowska-Grospierre B, Griscelli C, Doyle C, Mannhalter J, Eibl M, Glimcher LH (1991). "An HLA-DR alpha promoter DNA-binding protein is expressed ubiquitously and maps to human chromosomes 22 and 5". Immunogenetics 34 (5): 286–92. doi:10.1007/BF00211992. PMID 1718857.
4. Yoshida H, Nadanaka S, Sato R, Mori K (2006). "XBP1 is critical to protect cells from endoplasmic reticulum stress: evidence from Site-2 protease-deficient Chinese hamster ovary cells". Cell Structure and Function 31 (2): 117–25. doi:10.1247/csf.06016. PMID 17110785.
5. Ono SJ, Liou HC, Davidon R, Strominger JL, Glimcher LH (May 1991). "Human X-box-binding protein 1 is required for the transcription of a subset of human class II major histocompatibility genes and forms a heterodimer with c-fos". Proceedings of the National Academy of Sciences of the United States of America 88 (10): 4309–12. doi:10.1073/pnas.88.10.4309. PMC 51648. PMID 1903538.
6. Iwakoshi NN, Lee AH, Vallabhajosyula P, Otipoby KL, Rajewsky K, Glimcher LH (April 2003). "Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1". Nature Immunology 4 (4): 321–9. doi:10.1038/ni907. PMID 12612580.
7. Hu CC, Dougan SK, McGehee AM, Love JC, Ploegh HL (June 2009). "XBP-1 regulates signal transduction, transcription factors and bone marrow colonization in B cells". The EMBO Journal 28 (11): 1624–36. doi:10.1038/emboj.2009.117. PMC 2684024. PMID 19407814.
8. Bettigole SE, Lis R, Adoro S, Lee AH, Spencer LA, Weller PF, Glimcher LH (August 2015). "The transcription factor XBP1 is selectively required for eosinophil differentiation". Nature Immunology 16 (8): 829–37. doi:10.1038/ni.3225. PMC 4577297. PMID 26147683.
9. Zeng L, Xiao Q, Chen M, Margariti A, Martin D, Ivetic A, Xu H, Mason J, Wang W, Cockerill G, Mori K, Li JY, Chien S, Hu Y, Xu Q (April 2013). "Vascular endothelial cell growth-activated XBP1 splicing in endothelial cells is crucial for angiogenesis". Circulation 127 (16): 1712–22. doi:10.1161/CIRCULATIONAHA.112.001337. PMID 23529610.
10. Martin D, Li Y, Yang J, Wang G, Margariti A, Jiang Z, Yu H, Zampetaki A, Hu Y, Xu Q, Zeng L (October 2014). "Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3". The Journal of Biological Chemistry 289 (44): 30625–34. doi:10.1074/jbc.M114.571984. PMC 4215241. PMID 25190803.
11. Kaufman RJ (May 1999). "Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls". Genes & Development 13 (10): 1211–33. doi:10.1101/gad.13.10.1211. PMID 10346810.
12. Kober L, Zehe C, Bode J (October 2012). "Development of a novel ER stress based selection system for the isolation of highly productive clones". Biotechnology and Bioengineering 109 (10): 2599–611. doi:10.1002/bit.24527. PMID 22510960.
13. Casas-Tinto S, Zhang Y, Sanchez-Garcia J, Gomez-Velazquez M, Rincon-Limas DE, Fernandez-Funez P (June 2011). "The ER stress factor XBP1s prevents amyloid-beta neurotoxicity". Human Molecular Genetics 20 (11): 2144–60. doi:10.1093/hmg/ddr100. PMC 3090193. PMID 21389082.
14. Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS (September 2008). "XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease". Cell 134 (5): 743–56. doi:10.1016/j.cell.2008.07.021. PMC 2586148. PMID 18775308.
15. Kusumi I, Masui T, Kakiuchi C, Suzuki K, Akimoto T, Hashimoto R, Kunugi H, Kato T, Koyama T (December 2005). "Relationship between XBP1 genotype and personality traits assessed by TCI and NEO-FFI". Neuroscience Letters 391 (1-2): 7–10. doi:10.1016/j.neulet.2005.08.023. PMID 16154272.
16. Ding L, Yan J, Zhu J, Zhong H, Lu Q, Wang Z, Huang C, Ye Q (September 2003). "Ligand-independent activation of estrogen receptor alpha by XBP-1". Nucleic Acids Research 31 (18): 5266–74. doi:10.1093/nar/gkg731. PMC 203316. PMID 12954762.