PathwayStep4036 Translation and translocation of XBP1(S) to the Nucleus Cleavage of Xbp1 mRNA by IRE1alpha and Splicing of Cleaved Xbp1 mRNA ADP Binding by Phosphorylated IRE1 Homodimer Dimerization of IRE1 Autophosphorylation of IRE1 dimer Dissociation of IRE1:BiP heterodimer Activation of Chaperone Genes by XBP1(S) Activation of Chaperones by IRE1alpha Authored: May, B, 2009-06-02 00:51:49 Edited: May, B, Gopinathrao, G, 2008-11-19 19:22:37 GENE ONTOLOGYGO:0006987 IRE1-alpha is a single-pass transmembrane protein that resides in the endoplasmic reticulum (ER) membrane. The C-terminus of IRE1-alpha is located in the cytosol; the N-terminus is located in the ER lumen. In unstressed cells IRE1-alpha exists in an inactive heterodimeric complex with BiP such that BiP in the ER lumen binds the N-terminal region of IRE1-alpha. Upon accumulation of unfolded proteins in the ER, BiP binds the unfolded protein and the IRE1-alpha:BiP complex dissociates. The dissociated IRE1-alpha then forms homodimers. Initially the luminal N-terminal regions pair. This is followed by trans-autophosphorylation of IRE1-alpha at Ser724 in the cytosolic C-terminal region. The phosphorylation causes a conformational change that allows the dimer to bind ADP, causing a further conformational change to yield back-to-back pairing of the cytosolic C-terminal regions of IRE1-alpha. The fully paired IRE1-alpha homodimer has endoribonuclease activity and cleaves the mRNA encoding Xbp-1. A 26 residue polyribonucleotide is released and the 5' and 3' fragments of the original Xbp-1 mRNA are rejoined. The spliced Xbp-1 message encodes Xbp-1 (S), a potent activator of transcription. Xbp-1 (S) together with the ubiquitous transcription factor NF-Y bind the ER Stress Responsive Element (ERSE) in a number of genes encoding chaperones. Recent data suggest that the IRE1-alpha homodimer can also cleave specific subsets of mRNAs, including the insulin (INS) mRNA in pancreatic beta cells. Pubmed18038217 Pubmed18048764 Pubmed18436705 Reactome Database ID Release 43381070 Reactome, http://www.reactome.org ReactomeREACT_18368 Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 Reviewed: Urano, F, 2010-04-30 PathwayStep3989 PathwayStep3987 PathwayStep3988 PathwayStep3985 PathwayStep3986 PathwayStep3990