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{{Infobox_gene}}
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'''X-box binding protein 1''', also known as '''XBP1''', is a [[protein]] which in humans is encoded by the ''XBP1''  [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: XBP1 X-box binding protein 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7494| accessdate = }}</ref><ref name="pmid2321018">{{cite journal | vauthors = Liou HC, Boothby MR, Finn PW, Davidon R, Nabavi N, Zeleznik-Le NJ, Ting JP, Glimcher LH | title = A new member of the leucine zipper class of proteins that binds to the HLA DR alpha promoter | journal = Science | volume = 247 | issue = 4950 | pages = 1581–4 | date = March 1990 | pmid = 2321018 | doi = 10.1126/science.2321018 }}</ref> The ''XBP1'' gene is located on [[chromosome 22]] while a closely related [[pseudogene]] has been identified and localized to [[chromosome 5]].<ref name="pmid1718857">{{cite journal | vauthors = Liou HC, Eddy R, Shows T, Lisowska-Grospierre B, Griscelli C, Doyle C, Mannhalter J, Eibl M, Glimcher LH | title = An HLA-DR alpha promoter DNA-binding protein is expressed ubiquitously and maps to human chromosomes 22 and 5 | journal = Immunogenetics | volume = 34 | issue = 5 | pages = 286–92 | year = 1991 | pmid = 1718857 | doi = 10.1007/BF00211992 }}</ref> The XBP1 protein is a [[transcription factor]] that regulates the [[gene expression|expression]] of genes important to the proper functioning of the [[immune system]] and in the cellular stress response.<ref name="pmid17110785">{{cite journal | vauthors = Yoshida H, Nadanaka S, Sato R, Mori K | title = XBP1 is critical to protect cells from endoplasmic reticulum stress: evidence from Site-2 protease-deficient Chinese hamster ovary cells | journal = Cell Structure and Function | volume = 31 | issue = 2 | pages = 117–25 | year = 2006 | pmid = 17110785 | doi = 10.1247/csf.06016 }}</ref>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Discovery ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =  
| Name = X-box binding protein 1
| HGNCid = 12801
| Symbol = XBP1
| AltSymbols =; TREB5; XBP2
| OMIM = 194355
| ECnumber = 
| Homologene = 3722
| MGIid = 98970
| GeneAtlas_image1 = PBB_GE_XBP1_200670_at_tn.png
| Function = {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0043565 |text = sequence-specific DNA binding}} {{GNF_GO|id=GO:0046983 |text = protein dimerization activity}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006955 |text = immune response}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 7494
    | Hs_Ensembl = ENSG00000100219
    | Hs_RefseqProtein = NP_001073007
    | Hs_RefseqmRNA = NM_001079539
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 22
    | Hs_GenLoc_start = 27520549
    | Hs_GenLoc_end = 27526560
    | Hs_Uniprot = P17861
    | Mm_EntrezGene = 22433
    | Mm_Ensembl = ENSMUSG00000020484
    | Mm_RefseqmRNA = NM_013842
    | Mm_RefseqProtein = NP_038870
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 11
    | Mm_GenLoc_start = 5420970
    | Mm_GenLoc_end = 5425892
    | Mm_Uniprot = O35426
  }}
}}
'''X-box binding protein 1''', also known as '''XBP1''', is a human [[gene]].


==Function==
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 [[promoter (biology)#Promoter elements|transcriptional element]] in the [[promotor (biology)|promoter]] of the [[human leukocyte antigen]] (HLA) [[HLA-DRA|DR alpha]].<ref name="pmid2321018"/>
The transcription factor X-box binding protein 1 (XBP-1) is a bZIP transcription factor first identified by its ability to bind to the x-box, a conserved transcriptional element, in the human leukocyte antigen (HLA) DR alpha promoter. XBP-1 is also essential for plasma cell differentiation.  This differentiation requires not only the expression of XBP-1 but the expression of the spliced isoform of XBP-1s.  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 sarcoma-associated herpesvirus and Epstein Barr virus reactivation from latency.


XBP-1 is upregulated as part of the 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 autophosphorylation. 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.
== Function ==


Finally, a pseudogene has been identified and localized to chromosome 5.<ref name="entrez">{{cite web | title = Entrez Gene: XBP1 X-box binding protein 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7494| accessdate = }}</ref>
=== MHC class II gene regulation ===


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
The expression of this protein is required for the transcription of a subset of [[MHC class II|class II major histocompatibility]] genes.<ref name="pmid1903538">{{cite journal | vauthors = Ono SJ, Liou HC, Davidon R, Strominger JL, Glimcher LH | title = 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 10 | pages = 4309–12 | date = May 1991 | pmid = 1903538 | pmc = 51648 | doi = 10.1073/pnas.88.10.4309 | url = http://www.pnas.org/content/88/10/4309.abstract }}</ref>  Furthermore, XBP1 heterodimerizes with other bZIP transcription factors such as [[c-fos]].<ref name="pmid1903538"/>
{{PBB_Summary
| section_title =  
| summary_text = }}


==References==
XBP1 expression is controlled by the [[cytokine]] [[interleukin 4|IL-4]] and the antibody [[IGHM]].<ref name="pmid12612580">{{cite journal | vauthors = Iwakoshi NN, Lee AH, Vallabhajosyula P, Otipoby KL, Rajewsky K, Glimcher LH | title = Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1 | journal = Nature Immunology | volume = 4 | issue = 4 | pages = 321–9 | date = April 2003 | pmid = 12612580 | doi = 10.1038/ni907 }}</ref> XBP1 in turn controls the expression of [[interleukin 6|IL-6]] which promotes plasma cell growth and of [[antibody|immunoglobulins]] in [[B lymphocyte]]s.<ref name="pmid12612580"/>
{{reflist|2}}
==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal  | author=Clarke R, Liu MC, Bouker KB, ''et al.'' |title=Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. |journal=Oncogene |volume=22 |issue= 47 |pages= 7316-39 |year= 2003 |pmid= 14576841 |doi= 10.1038/sj.onc.1206937 }}
*{{cite journal  | author=Nekrutenko A, He J |title=Functionality of unspliced XBP1 is required to explain evolution of overlapping reading frames. |journal=Trends Genet. |volume=22 |issue= 12 |pages= 645-8 |year= 2007 |pmid= 17034899 |doi= 10.1016/j.tig.2006.09.012 }}
*{{cite journal  | author=Liou HC, Eddy R, Shows T, ''et al.'' |title=An HLA-DR alpha promoter DNA-binding protein is expressed ubiquitously and maps to human chromosomes 22 and 5. |journal=Immunogenetics |volume=34 |issue= 5 |pages= 286-92 |year= 1991 |pmid= 1718857 |doi=  }}
*{{cite journal  | author=Ono SJ, Liou HC, Davidon R, ''et al.'' |title=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. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=88 |issue= 10 |pages= 4309-12 |year= 1991 |pmid= 1903538 |doi=  }}
*{{cite journal  | author=Yoshimura T, Fujisawa J, Yoshida M |title=Multiple cDNA clones encoding nuclear proteins that bind to the tax-dependent enhancer of HTLV-1: all contain a leucine zipper structure and basic amino acid domain. |journal=EMBO J. |volume=9 |issue= 8 |pages= 2537-42 |year= 1990 |pmid= 2196176 |doi=  }}
*{{cite journal  | author=Liou HC, Boothby MR, Finn PW, ''et al.'' |title=A new member of the leucine zipper class of proteins that binds to the HLA DR alpha promoter. |journal=Science |volume=247 |issue= 4950 |pages= 1581-4 |year= 1990 |pmid= 2321018 |doi= }}
*{{cite journal | author=Ponath PD, Fass D, Liou HC, ''et al.'' |title=The regulatory gene, hXBP-1, and its target, HLA-DRA, utilize both common and distinct regulatory elements and protein complexes. |journal=J. Biol. Chem. |volume=268 |issue= 23 |pages= 17074-82 |year= 1993 |pmid= 8349596 |doi=  }}
*{{cite journal  | author=Clauss IM, Chu M, Zhao JL, Glimcher LH |title=The basic domain/leucine zipper protein hXBP-1 preferentially binds to and transactivates CRE-like sequences containing an ACGT core. |journal=Nucleic Acids Res. |volume=24 |issue= 10 |pages= 1855-64 |year= 1996 |pmid= 8657566 |doi=  }}
*{{cite journal  | author=Kishimoto T, Kokura K, Ohkawa N, ''et al.'' |title=Enhanced expression of a new class of liver-enriched b-Zip transcription factors, hepatocarcinogenesis-related transcription factor, in hepatocellular carcinomas of rats and humans. |journal=Cell Growth Differ. |volume=9 |issue= 4 |pages= 337-44 |year= 1998 |pmid= 9563853 |doi=  }}
*{{cite journal  | author=Dunham I, Shimizu N, Roe BA, ''et al.'' |title=The DNA sequence of human chromosome 22. |journal=Nature |volume=402 |issue= 6761 |pages= 489-95 |year= 1999 |pmid= 10591208 |doi= 10.1038/990031 }}
*{{cite journal  | author=Reimold AM, Etkin A, Clauss I, ''et al.'' |title=An essential role in liver development for transcription factor XBP-1. |journal=Genes Dev. |volume=14 |issue= 2 |pages= 152-7 |year= 2000 |pmid= 10652269 |doi=  }}
*{{cite journal  | author=Hartley JL, Temple GF, Brasch MA |title=DNA cloning using in vitro site-specific recombination. |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788-95 |year= 2001 |pmid= 11076863 |doi=  }}
*{{cite journal  | author=Yoshida H, Matsui T, Yamamoto A, ''et al.'' |title=XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. |journal=Cell |volume=107 |issue= 7 |pages= 881-91 |year= 2002 |pmid= 11779464 |doi=  }}
*{{cite journal  | author=Takahashi S, Suzuki S, Inaguma S, ''et al.'' |title=Down-regulation of human X-box binding protein 1 (hXBP-1) expression correlates with tumor progression in human prostate cancers. |journal=Prostate |volume=50 |issue= 3 |pages= 154-61 |year= 2002 |pmid= 11813207 |doi=  }}
*{{cite journal  | author=Gu Z, Lee RY, Skaar TC, ''et al.'' |title=Association of interferon regulatory factor-1, nucleophosmin, nuclear factor-kappaB, and cyclic AMP response element binding with acquired resistance to Faslodex (ICI 182,780). |journal=Cancer Res. |volume=62 |issue= 12 |pages= 3428-37 |year= 2002 |pmid= 12067985 |doi=  }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
*{{cite journal  | author=Yoshida H, Matsui T, Hosokawa N, ''et al.'' |title=A time-dependent phase shift in the mammalian unfolded protein response. |journal=Dev. Cell |volume=4 |issue= 2 |pages= 265-71 |year= 2003 |pmid= 12586069 |doi=  }}
*{{cite journal  | author=Shuda M, Kondoh N, Imazeki N, ''et al.'' |title=Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. |journal=J. Hepatol. |volume=38 |issue= 5 |pages= 605-14 |year= 2004 |pmid= 12713871 |doi=  }}
*{{cite journal  | author=Newman JR, Keating AE |title=Comprehensive identification of human bZIP interactions with coiled-coil arrays. |journal=Science |volume=300 |issue= 5628 |pages= 2097-101 |year= 2003 |pmid= 12805554 |doi= 10.1126/science.1084648 }}
*{{cite journal  | author=Kakiuchi C, Iwamoto K, Ishiwata M, ''et al.'' |title=Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. |journal=Nat. Genet. |volume=35 |issue= 2 |pages= 171-5 |year= 2003 |pmid= 12949534 |doi= 10.1038/ng1235 }}
}}
{{refend}}


{{gene-22-stub}}
=== Plasma cell differentiation ===
{{Transcription factors}}
 
[[Category:Transcription factors]]
XBP1 is also essential for [[cellular differentiation|differentiation]] of [[plasma cell]]s (a type of antibody secreting immune cell).<ref name="pmid12612580"/>  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).<ref name="pmid19407814">{{cite journal | vauthors = Hu CC, Dougan SK, McGehee AM, Love JC, Ploegh HL | title = XBP-1 regulates signal transduction, transcription factors and bone marrow colonization in B cells | journal = The EMBO Journal | volume = 28 | issue = 11 | pages = 1624–36 | date = June 2009 | pmid = 19407814 | pmc = 2684024 | doi = 10.1038/emboj.2009.117 }}</ref>  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.<ref name="pmid19407814"/>
{{WikiDoc Sources}}
 
=== Eosinophil differentiation ===
XBP1 is required for [[eosinophil]] differentiation. Eosinophils lacking XBP1 exhibit defects in granule proteins.<ref>{{cite journal | vauthors = Bettigole SE, Lis R, Adoro S, Lee AH, Spencer LA, Weller PF, Glimcher LH | title = The transcription factor XBP1 is selectively required for eosinophil differentiation | journal = Nature Immunology | volume = 16 | issue = 8 | pages = 829–37 | date = August 2015 | pmc = 4577297 | doi = 10.1038/ni.3225 | pmid = 26147683 }}</ref>
 
=== Angiogenesis ===
XBP1 acts to regulate endothelial cell proliferation through growth factor pathways,<ref>{{cite journal | vauthors = 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 | title = Vascular endothelial cell growth-activated XBP1 splicing in endothelial cells is crucial for angiogenesis | journal = Circulation | volume = 127 | issue = 16 | pages = 1712–22 | date = April 2013 | doi = 10.1161/CIRCULATIONAHA.112.001337 | pmid = 23529610  }}</ref> leading to [[angiogenesis]]. Additionally, XBP1 protects endothelial cells from oxidative stress by interacting with [[HDAC3]].<ref>{{cite journal | vauthors = Martin D, Li Y, Yang J, Wang G, Margariti A, Jiang Z, Yu H, Zampetaki A, Hu Y, Xu Q, Zeng L | title = Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3 | journal = The Journal of Biological Chemistry | volume = 289 | issue = 44 | pages = 30625–34 | date = October 2014 | pmc = 4215241 | doi = 10.1074/jbc.M114.571984 | pmid = 25190803  }}</ref>
 
=== 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).<ref name="pmid12612580"/> Conditions that exceed capacity of the ER provoke [[Endoplasmic reticulum#Endoplasmic reticulum stress|ER stress]] and trigger the unfolded protein response (UPR). As a result, [[Binding immunoglobulin protein|GRP78]] is released from IRE1 to support protein folding.<ref name="pmid10346810">{{cite journal | vauthors = Kaufman RJ | title = Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls | journal = Genes & Development | volume = 13 | issue = 10 | pages = 1211–33 | date = May 1999 | pmid = 10346810 | doi = 10.1101/gad.13.10.1211 | url = http://genesdev.cshlp.org/content/13/10/1211.long }}</ref> 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.<ref name="pmid22510960">{{cite journal | vauthors = Kober L, Zehe C, Bode J | title = Development of a novel ER stress based selection system for the isolation of highly productive clones | journal = Biotechnology and Bioengineering | volume = 109 | issue = 10 | pages = 2599–611 | date = October 2012 | pmid = 22510960 | doi = 10.1002/bit.24527 }}</ref>
 
== 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]].<ref name=pmid21389082>{{cite journal | vauthors = Casas-Tinto S, Zhang Y, Sanchez-Garcia J, Gomez-Velazquez M, Rincon-Limas DE, Fernandez-Funez P | title = The ER stress factor XBP1s prevents amyloid-beta neurotoxicity | journal = Human Molecular Genetics | volume = 20 | issue = 11 | pages = 2144–60 | date = June 2011 | pmid = 21389082 | pmc = 3090193 | doi = 10.1093/hmg/ddr100 }}</ref>  In the [[Colon (anatomy)|colon]], XBP1 anomalies have been linked to [[Crohn's disease]].<ref name="pmid18775308">{{cite journal | vauthors = Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS | title = XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease | journal = Cell | volume = 134 | issue = 5 | pages = 743–56 | date = September 2008 | pmid = 18775308 | pmc = 2586148 | doi = 10.1016/j.cell.2008.07.021 }}</ref>
 
A [[single nucleotide polymorphism]], C-116G, in the promoter region of ''XBP1'' has been examined for possible associations with [[personality trait]]s. None were found.<ref name="pmid16154272">{{cite journal | vauthors = Kusumi I, Masui T, Kakiuchi C, Suzuki K, Akimoto T, Hashimoto R, Kunugi H, Kato T, Koyama T | title = Relationship between XBP1 genotype and personality traits assessed by TCI and NEO-FFI | journal = Neuroscience Letters | volume = 391 | issue = 1-2 | pages = 7–10 | date = December 2005 | pmid = 16154272 | doi = 10.1016/j.neulet.2005.08.023 }}</ref>
 
== Interactions ==
 
XBP1 has been shown to [[Protein-protein interaction|interact]] with [[estrogen receptor alpha]].<ref name="pmid12954762">{{cite journal | vauthors = Ding L, Yan J, Zhu J, Zhong H, Lu Q, Wang Z, Huang C, Ye Q | title = Ligand-independent activation of estrogen receptor alpha by XBP-1 | journal = Nucleic Acids Research | volume = 31 | issue = 18 | pages = 5266–74 | date = September 2003 | pmid = 12954762 | pmc = 203316 | doi = 10.1093/nar/gkg731 }}</ref>
 
== See also ==
* [[Unfolded protein response]]
 
== References ==
{{Reflist|33em}}
 
{{Transcription factors|g1}}

Revision as of 10:12, 1 November 2017

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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, 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.[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

References

  1. ↑ "Entrez Gene: XBP1 X-box binding protein 1".
  2. ↑ 2.0 2.1 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. ↑ 5.0 5.1 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. ↑ 6.0 6.1 6.2 6.3 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. ↑ 7.0 7.1 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.
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