XBP1
Overview
X-box binding protein 1, also known as XBP1, is a protein which in humans is encoded by the XBP1 gene. The XBP1 gene is located on chromosome 22 while a closely related pseudogene has been identified and localized to chromosome 5.] 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 (1)
Endoplasmic reticulum (ER) stress is increasingly recognized as an important mechanism in a wide range of diseases including cystic fibrosis, alpha-1 antitrypsin deficiency, Parkinson's and Alzheimer's disease. Therefore, there is an increased need for reliable and quantitative markers for detection of ER stress in human tissues and cells. Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum can cause ER stress, which leads to the activation of the unfolded protein response (UPR). UPR signaling involves splicing of X-box binding protein-1 (XBP1) mRNA, which is frequently used as a marker for ER stress. In most studies, the splicing of the XBP1 mRNA is visualized by gel electrophoresis which is laborious and difficult to quantify. (2)
Endoplasmic reticulum (ER) stress induced by protein misfolding is an important mechanism in cellular stress in a variety of diseases. When protein folding in the ER is compromised, the unfolded proteins accumulate in the ER which leads to ER stress. ER stress triggers the unfolded protein response (UPR), a transcriptional induction pathway which is aimed at restoring normal ER functioning (3)
The UPR is mediated by three ER stress receptors: protein kinase RNA-like ER kinase (PERK), inositol-requiring protein-1 (IRE1) and activating transcription factor-6 (ATF6). In the absence of ER stress, all three ER stress receptors are maintained in an inactive state through their association with the ER-chaperone protein GRP78 (BiP). ER stress results in the dissociation of BiP from the three receptors, which subsequently leads to their activation (Ron and Walter 2007). Dissociation of BiP from PERK leads to autophoshorylation and thereby activation of PERK and subsequent phosphorylation of translation initiation factor eIF2α, resulting in an inhibition of mRNA translation, and eventually in the translation of the transcription factor ATF4. Dissociation of BiP from ATF6 leads to translocation of ATF6 to the Golgi complex where it is cleaved by proteases into an active transcription factor. Active ATF6 moves to the nucleus and induces expression of genes with an ER stress response element (ERSE) in their promoter such as the ER-chaperone protein BiP and the transcription factors C/EBP homologous protein (CHOP) and X-box binding protein-1 (XBP1). Dissociation of BiP from IRE1 leads to the activation of IRE1 which cleaves a 26-nucleotide intron from the XBP1 mRNA. The spliced XBP1 mRNA encodes a stable, active transcription factor that binds to the UPRE or ERSE sequence of many UPR target genes, leading to transcription of ER-chaperone proteins (4)
Functions
MHC class II gene regulation
The expression of this protein is required for the transcription of a subset of class II major histocompatibility genes.Furthermore, XBP1 heterodimerizes with other bZIP transcription factors such as c-fos
XBP1 expression is controlled by the cytokine IL-4 and the antibody IGHM. XBP1 in turn controls the expression of IL-6 which promotes plasma cell growth and of immunoglobulins in B lymphocytes. (5,6)
Plasma cell differentiation
XBP1 is also essential for differentiation of plasma cells (a type of antibody secreting immune cell). 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)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.(5,6)
Eosinophil differentiation
XBP1 is required for eosinophil differentiation. Eosinophils lacking XBP1 exhibit defects in granule proteins. (6)
Angiogenesis
XBP1 acts to regulate endothelial cell proliferation through growth factor pathways,leading to angiogenesis. Additionally, XBP1 protects endothelial cells from oxidative stress by interacting with HDAC3.(7,8)
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. (7,8)
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. 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 (8,9)
Relevance
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 and polymyositis
Article by Dr. JOSE PEREIRA, MD
Footnotes:
- Hirota M, .Quantitative measurement of spliced XBP1 mRNA as an indicator of endoplasmic reticulum stress. J Toxicol Sci. 2006;31:149–156. doi: 10.2131/jts.31.149. [PubMed] [Cross Ref]
- Ron D,. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8:519–529. doi: 10.1038/nrm2199. [PubMed] [Cross Ref]
- Rutkowski DT. A trip to the ER: coping with stress. Trends Cell Biol. 2004;14:20–28. doi: 10.1016/j.tcb.2003.11.001. [PubMed] [Cross Ref]
- Samali A,. Methods for monitoring endoplasmic reticulum stress and the unfolded protein response. Int J Cell Biol. 2010;2010:830307. [PMC free article] [PubMed]
- Schroder M,. The mammalian unfolded protein response. Annu Rev Biochem. 2005;74:739–789. doi: 10.1146/annurev.biochem.73.011303.074134. [PubMed] [Cross Ref]
- Wetering S,. Regulation of secretory leukocyte proteinase inhibitor (SLPI) production by human bronchial epithelial cells: increase of cell-associated SLPI by neutrophil elastase. J Investig Med. 2000;48:359–366. [PubMed]
- Vandesompele J,. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3:RESEARCH0034. doi: 10.1186/gb-2002-3-7-research0034. [PMC free article] [PubMed] [Cross Ref]
- Yoshida H,. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107:881–891. doi: 10.1016/S0092-8674(01)00611-0. [PubMed] [Cross Ref]
- Zhao H,. Measuring the impact of cigarette smoke on the UPR. Methods Enzymol. 2011;489:147–164. doi: 10.1016/B978-0-12-385116-1.00009-1. [PubMed] [Cross Ref]
