XBP1

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X-box binding protein 1
Identifiers
Symbols XBP1 ; TREB5; XBP-1; XBP2
External IDs OMIM194355 MGI98970 HomoloGene3722 ChEMBL: 1741176 GeneCards: XBP1 Gene
RNA expression pattern
PBB GE XBP1 200670 at tn.png
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:
29.19 – 29.2 Mb
Chr 11:
5.52 – 5.53 Mb
PubMed search [1] [2]

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[edit]

The X-box binding protein 1 (XBP-1) is a transcription factor 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.[2]

Function[edit]

MHC class II gene regulation[edit]

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[edit]

XBP-1 is also essential for differentiation of plasma cells (a type of antibody secreting immune cell).[6] 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).[7] 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.[7]

Viral replication[edit]

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.

Endoplasmic reticulum stress response[edit]

XBP-1 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.[8] 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 XBP-1u 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 376 amino acid, 54 kDa, XBP-1s isoform rather than the 261 amino acid, 33 kDa, XBP-1u isoform. Moreover the XBP-1u/XBP-1s ratio correlates with the expression level of expressed proteins in order to adapt the folding capacity of the ER to the respective requirements.[9]

Clinical significance[edit]

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.[10] In the colon, XBP1 anomalies have been linked to Crohn's disease.[11]

A single nucleotide polymorphism, C-116G, in the promoter region of XBP1 has been examined for possible association with personality traits. None was found.[12]

Interactions[edit]

XBP1 has been shown to interact with estrogen receptor alpha.[13]

See also[edit]

References[edit]

  1. ^ "Entrez Gene: XBP1 X-box binding protein 1". 
  2. ^ a b 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. ^ a b 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". Proc. Natl. Acad. Sci. U.S.A. 88 (10): 4309–12. doi:10.1073/pnas.88.10.4309. PMC 51648. PMID 1903538. 
  6. ^ a b c d 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". Nat. Immunol. 4 (4): 321–9. doi:10.1038/ni907. PMID 12612580. 
  7. ^ a b Hu CC, Dougan SK, McGehee AM, Love JC, Ploegh HL (April 2009). "XBP-1 regulates signal transduction, transcription factors and bone marrow colonization in B cells". EMBO J. 28 (11): 1624–36. doi:10.1038/emboj.2009.117. PMC 2684024. PMID 19407814. 
  8. ^ Kaufman RJ (May 1999). "Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls". Genes Dev. 13 (10): 1211–33. doi:10.1101/gad.13.10.1211. PMID 10346810. 
  9. ^ Kober L, Zehe C, Bode J (October 2012). "Development of a novel ER stress based selection system for the isolation of highly productive clones". Biotechnol. Bioeng. 109 (10): 2599–611. doi:10.1002/bit.24527. PMID 22510960. 
  10. ^ Casas-Tinto, S; Zhang, Y, Sanchez-Garcia, J, Gomez-Velazquez, M, Rincon-Limas, DE, Fernandez-Funez, P (25 March 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. 
  11. ^ 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. 
  12. ^ 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". Neurosci. Lett. 391 (1–2): 7–10. doi:10.1016/j.neulet.2005.08.023. PMID 16154272. 
  13. ^ 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 Res. 31 (18): 5266–74. doi:10.1093/nar/gkg731. PMC 203316. PMID 12954762.