The IRE1 pathway Sample Clauses

The IRE1 pathway. The IRE1 pathway is a branch of the UPR conserved from yeast to mammals (Xx et al., 2014). IRE1 was first described in S. cerevisiae as a dysfunctional mutant that required inositol to grow (Cox et al., 1993; Xxxxx et al., 2013). IRE1 is a type IV transmembrane protein that resides within the ER membrane. It has an N-terminal luminal sensor domain and a C-terminal cytosolic effector domain with kinase and endoribonuclease activity (Xxxxxx et al., 2002; Xxxxxx and Xxx, 2011). The sensor has two isoforms, IRE1α and IRE1β. The first is ubiquitously expressed, the latter only in gut epithelial cells (Boot-Xxxxxxxx and Xxxxxx, 2009). In mammals, IRE1α and IRE1β share a structural similarity but are functionally different. IRE1β catalyses the site specific cleavage of 28sRNA, effectively attenuating translation (Xxxxxxxxxx et al., 1998; Xxxxxxx et al., 2001). IRE1α mediates the non-conventional splicing of X-box binding protein 1 (XBP1) mRNA (Xxxxxx et al., 2002) and controls its own expression by cleaving IRE1 mRNA (Xxxxxxxxxx et al., 1998). The capacity of IRE1α to sense ER stress is dependent on its association with the ER chaperone binding immunoglobulin protein (BiP; also known as 78kDa glucose-regulated protein, GRP78) and its ability to bind unfolded proteins directly. Under normal conditions BiP/GRP78 is bound to IRE1α keeping the protein in an inactive monomeric state (Xxxxxxxxxx et al., 2000; Xxxxxx et al., 2003; Xxxxxx et al., 2009). Under ER stress conditions, BiP/GRP78 binds prefentially to unfolded proteins. The dissociation of BiP/GRP78 from IRE1α leads to its multimerisation, autophosphorylation and activation of RNase activity (Xxxx and Xxxxxxxx, 2009; Xxxxxx et al., 2009). Upon IRE1α activation the ER luminal stress signal is transferred to the cytoplasm and the nucleus leading to the activation of several signalling pathways (Xxxxx et al., 2011; Xxxxx et al., 2013). IRE1α’s RNase activity is responsible for the non-conventional splicing of XBP1 mRNA, excising a 26 nucleotide sequence, causing a reading frame shift and creating XBP1s (Xxxxxxx et al., 2001; Xxxxxx et al., 2002). The translation of XBP1s results in a protein that is a strong transactivator of genes involved in ER protein quality control, protein folding, degradation processes and ER and Golgi apparatus biogenesis (Xxx and Xxxxxx, 2007; Xxxxxx and Xxx, 2011). Unspliced XBP1 has no transcriptional function but functions as a negative feedback regulator of XBP1s by sequestering it f...