XBP1

X-box binding protein 1, also known as XBP1, is a protein which in humans is encoded by the XBP1 gene.[5][6] The XBP1 gene is located on chromosome 22 while a closely related pseudogene has been identified and localized to chromosome 5.[7] 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.[8]

XBP1
Identifiers
Aliases	XBP1, TREB5, XBP-1, XBP2, TREB-5, X-box binding protein 1
External IDs	OMIM: 194355 MGI: 98970 HomoloGene: 3722 GeneCards: XBP1
Gene location (Human) Chr. Chromosome 22 (human)[1] Band 22q12.1|22q12 Start 28,794,555 bp[1] End 28,800,597 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11 A1|11 3.61 cM Start 5,520,659 bp[2] End 5,525,893 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • estrogen receptor binding • protein homodimerization activity • RNA polymerase II transcription factor binding • protease binding • GO:0001948 protein binding • protein kinase binding • sequence-specific DNA binding • GO:0001158 core promoter proximal region sequence-specific DNA binding • protein heterodimerization activity • chromatin DNA binding • ubiquitin protein ligase binding • DNA binding • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • RNA polymerase II regulatory region sequence-specific DNA binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding • identical protein binding Cellular component • cytosol • membrane • integral component of membrane • nucleoplasm • integral component of endoplasmic reticulum membrane • endoplasmic reticulum membrane • cytoplasm • endoplasmic reticulum • cell nucleus Biological process • positive regulation of MHC class II biosynthetic process • positive regulation of protein phosphorylation • negative regulation of endoplasmic reticulum unfolded protein response • positive regulation of immunoglobulin production • muscle organ development • vascular endothelial growth factor receptor signaling pathway • phosphatidylinositol 3-kinase signaling • apoptotic process • regulation of transcription, DNA-templated • regulation of protein stability • glucose homeostasis • transcription, DNA-templated • cell growth • positive regulation of endothelial cell apoptotic process • response to unfolded protein • fatty acid biosynthetic process • protein transport • positive regulation of TOR signaling • exocrine pancreas development • negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway • cell differentiation • positive regulation of autophagy • cellular response to laminar fluid shear stress • positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress • positive regulation of B cell differentiation • negative regulation of transcription from RNA polymerase II promoter • cellular response to fluid shear stress • organelle organization • regulation of autophagy • immune response • positive regulation of proteasomal protein catabolic process • positive regulation of plasma cell differentiation • positive regulation of T cell differentiation • positive regulation of endoplasmic reticulum unfolded protein response • positive regulation of histone methylation • lipid metabolism • epithelial cell maturation involved in salivary gland development • positive regulation of protein acetylation • positive regulation of ER-associated ubiquitin-dependent protein catabolic process • autophagy • multicellular organism development • ATF6-mediated unfolded protein response • IRE1-mediated unfolded protein response • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress • epithelial cell maturation • cellular response to oxidative stress • cellular response to vascular endothelial growth factor stimulus • protein destabilization • cellular response to peptide hormone stimulus • positive regulation of transcription from RNA polymerase II promoter • negative regulation of pathway-restricted SMAD protein phosphorylation • adipose tissue development • positive regulation of vascular associated smooth muscle cell migration • liver development • cellular triglyceride homeostasis • cholesterol homeostasis • negative regulation of transforming growth factor beta receptor signaling pathway • positive regulation of lactation • cellular response to amino acid stimulus • angiogenesis • cellular response to glucose starvation • response to insulin-like growth factor stimulus • negative regulation of ERK1 and ERK2 cascade • fatty acid homeostasis • positive regulation of vascular smooth muscle cell proliferation • positive regulation of hepatocyte proliferation • sterol homeostasis • cellular response to interleukin-4 • positive regulation of protein kinase B signaling • ubiquitin-dependent protein catabolic process • positive regulation of fat cell differentiation • negative regulation of apoptotic process • endothelial cell proliferation • transcription from RNA polymerase II promoter • positive regulation of cell proliferation • negative regulation of myotube differentiation • positive regulation of cell migration • endoplasmic reticulum unfolded protein response • cellular response to nutrient • cellular response to insulin stimulus • response to endoplasmic reticulum stress • positive regulation of vascular wound healing • positive regulation of angiogenesis • neuron development • positive regulation of immunoglobulin secretion • cellular response to lipopolysaccharide • cellular response to fructose stimulus • cellular response to glucose stimulus • positive regulation of interleukin-6 secretion • positive regulation of transcription from RNA polymerase II promoter involved in unfolded protein response • cellular response to leukemia inhibitory factor • positive regulation of protein import into nucleus • regulation of cell growth Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	7494	22433
Ensembl	ENSG00000100219	ENSMUSG00000020484
UniProt	P17861	O35426
RefSeq (mRNA)	NM_005080 NM_001079539	NM_001271730 NM_013842
RefSeq (protein)	NP_001073007 NP_005071	NP_001258659 NP_038870
Location (UCSC)	Chr 22: 28.79 – 28.8 Mb	Chr 11: 5.52 – 5.53 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[6]

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.[9] Furthermore, XBP1 heterodimerizes with other bZIP transcription factors such as c-fos.[9]

XBP1 expression is controlled by the cytokine IL-4 and the antibody IGHM.[10] XBP1 in turn controls the expression of IL-6 which promotes plasma cell growth and of immunoglobulins in B lymphocytes.[10]

Plasma cell differentiation

XBP1 is also essential for differentiation of plasma cells (a type of antibody secreting immune cell).[10] 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).[11] 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.[11]

Eosinophil differentiation

XBP1 is required for eosinophil differentiation. Eosinophils lacking XBP1 exhibit defects in granule proteins.[12]

Angiogenesis

XBP1 acts to regulate endothelial cell proliferation through growth factor pathways,[13] leading to angiogenesis. Additionally, XBP1 protects endothelial cells from oxidative stress by interacting with HDAC3.[14]

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.[15] 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).[10] 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.[16] 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, 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.[17]

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.[18] In the colon, XBP1 anomalies have been linked to Crohn's disease.[19]

A single nucleotide polymorphism, C116G, in the promoter region of XBP1 has been examined for possible associations with personality traits. None were found.[20]

Interactions

XBP1 has been shown to interact with estrogen receptor alpha.[21]

See also

• Unfolded protein response

References

1. GRCh38: Ensembl release 89: ENSG00000100219 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000020484 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: XBP1 X-box binding protein 1".
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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" (PDF). The EMBO Journal. 28 (11): 1624–36. doi:10.1038/emboj.2009.117. PMC 2684024. PMID 19407814.
12. 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.
13. 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.
14. 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.
15. Ku, SC (2008). "XBP-1, a novel human T-lymphotropic virus type 1 (HTLV-1) tax binding protein, activates HTLV-1 basal and tax-activated transcription". J Virol. 82 (9): 4343–53. doi:10.1128/JVI.02054-07. PMC 2293026. PMID 18287238.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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. hdl:2115/8420. PMID 16154272.
21. 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.