X-box binding protein 1, also known asXBP1, is aprotein which in humans is encoded by theXBP1gene.[5][6] TheXBP1 gene is located onchromosome 22 while a closely relatedpseudogene has been identified and localized tochromosome 5.[7] The XBP1 protein is atranscription factor that regulates theexpression of genes important to the proper functioning of theimmune system and in the cellular stress response.[8]
The expression of this protein is required for the transcription of a subset ofclass II major histocompatibility genes.[9] Furthermore, XBP1 heterodimerizes with other bZIP transcription factors such asc-fos.[9]
XBP1 is also essential fordifferentiation ofplasma 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]
This protein has also been identified as a cellular transcription factor that binds to an enhancer in the promoter of theHuman T-lymphotropic virus 1.[15] The generation of XBP1s during plasma cell differentiation also seems to be the cue forKaposi's sarcoma-associatedherpesvirus andEpstein Barr virus reactivation from latency.
XBP1 is part of theendoplasmic reticulum (ER) stress response and theunfolded protein response (UPR).[10] Conditions that exceed capacity of the ER provokeER 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 itsribonuclease domain through auto (self)phosphorylation. Activated IRE1 catalyses the excision of a 26 nucleotide unconventionalintron 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-1sisoform 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]
Abnormalities in XBP1 lead to a heightened ER stress and subsequently causes a heightened susceptibility for inflammatory processes that may contribute toAlzheimer's disease.[18] In thecolon, XBP1 anomalies have been linked toCrohn's disease.[19]
^abLiou HC, Boothby MR, Finn PW, Davidon R, Nabavi N, Zeleznik-Le NJ, et al. (March 1990). "A new member of the leucine zipper class of proteins that binds to the HLA DR alpha promoter".Science.247 (4950):1581–1584.Bibcode:1990Sci...247.1581L.doi:10.1126/science.2321018.PMID2321018.
^Liou HC, Eddy R, Shows T, Lisowska-Grospierre B, Griscelli C, Doyle C, et al. (1991). "An HLA-DR alpha promoter DNA-binding protein is expressed ubiquitously and maps to human chromosomes 22 and 5".Immunogenetics.34 (5):286–292.doi:10.1007/BF00211992.PMID1718857.S2CID2939108.
^abcdIwakoshi 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):321–329.doi:10.1038/ni907.PMID12612580.S2CID20161577.
^Kusumi I, Masui T, Kakiuchi C, Suzuki K, Akimoto T, Hashimoto R, et al. (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.PMID16154272.S2CID505223.
