While the three ER stress sensory proteins function in parallel, there is cross-regulation that serves to coordinate the timing and magnitude of the UPR. PERK (EIF2AK3) is the third UPR sensor, which phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α) to direct translational and transcriptional modes of gene expression that regulate ER processing of proteins, metabolism, and the oxidation status of cells ( 6, 10).
In response to ER stress, ATF6 transits from the ER to the Golgi apparatus, where it is cleaved, releasing an N-terminal cytosolic fragment (ATF6-N) that enters the nucleus and activates UPR target genes involved in protein folding and transport ( 6, 9). IRE1 (ERN1) is a protein kinase and endoribonuclease that facilitates cytosolic splicing of XBP1 (XBP1s) mRNA, thereby enhancing expression of the XBP1s isoform, which induces transcription of genes involved in ER-associated protein degradation (ERAD), lipid synthesis, and protein folding ( 7, 8). Three ER transmembrane proteins, IRE1, ATF6, and PERK, operate as sensors that activate the UPR, leading to changes in gene expression that restore and expand the processing capacity of the organelle ( 6 – 8). The ER is sensitive to the perturbations in protein homeostasis through a stress-sensing pathway known as the unfolded protein response (UPR).
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