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Background
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The endoplasmic reticulum (ER) is an organelle composed of an interconnected network of tubules, vesicles and cisternae found in all eukaryotic cells. It is involved in several specialized processes such as protein translation, folding, and transport of proteins to be used in the cell membrane or secreted from the cell. Accumulation of malfolded proteins in the ER activates the unfolded protein response (UPR) and the upregulation of the ER molecular chaperones GRP78 and GRP 94. These proteins are normally bound to ER transmembrane proteins such as IRE1p and ATF6 but ER stress causes their dissociation. This allows IRE1p, a serine-threonine protein kinase, to transduce the unfolded protein signal from the ER to the nucleus. IRE1p also has an endoribonuclease activity that is required to splice X-box binding protein (XBP1) mRNA, converting it to a potent UPR transcriptional activator. ER stress also causes the cleavage of ATF6, yielding a cytosolic fragment which migrates to the nucleus and together with XBP-1, activates transcription of UPR-responsive genes. Depletion of IRE1p through the expression of a dominant negative form of IRE1p has no effect on transfected cells, but cell death via apoptosis occurs under stress conditions that cause unfolded proteins to accumulate in the ER.
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