In response to ER stress, cells activate adaptive intracellular signal transduction pathways, known as the unfolded protein response (UPR), so that the cells can recover from the stress.
3 –5 Three ER-localized transmembrane protein sensors can initiate the UPR. These are inositol requiring kinase 1α (IRE1α), protein kinase-like ER kinase (PERK), and activating transcription factor 6α (ATF6α). The combined activation of IRE1α, PERK, and ATF6α initially produces cytoprotective outputs, such as enhanced ER protein folding capacity, reduced protein translation, and clearance of misfolded ER proteins.
6 For instance, the activated IRE1α endonuclease splices out a 26-nucleotide intron of
Xbp-1 mRNA, leading to a frameshift in codon reading and consequently creating an additional potent transactivation domain in the C terminus of the Xbp-1 protein.
7 Xbp-1 controls a large group of UPR-response genes, including the ER chaperone BiP, to cope with the unfolded protein load in the ER.
8,9 However, when cells undergo prolonged and severe ER stress and ER homeostasis cannot be reestablished, proapoptotic signals are triggered, presumably to protect the organism from these irreversibly damaged cells.
10,11 The molecular mechanisms of ER stress–induced cell death are not completely understood. The UPR signaling pathway induced by PERK can contribute to cell death. PERK phosphorylates eukaryotic initiation factor 2α (eIF2α), which results in the enhanced translation of ATF4, a b-ZIP transcription factor. One of the important UPR-specific target genes of ATF4 is
CHOP/GADD153, a b-ZIP transcription factor, which plays a role in apoptosis during ER stress.
12 –14