Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase
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...The principal branches of UPR signalling are mediated through three molecules: inositol-requiring enzyme 1 (IRE-1), PKR-like endoplasmic-reticulum kinase (PERK) and activating transcription factor 6 (ATF6...
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...Gcn4p is a transcription factor that binds to and acti-the mammalian eIF2 kinases PERK and GCN2 repress translation of most mRNAs but selectively increase vates the target genes of this pathway (Hinnebusch, 1997).translation of Activating Transcription Factor 4 (ATF4), resulting in the induction of the downstream gene The striking conservation in structure and function between mammalian and yeast eIF2a and eIF2a kinasesCHOP (GADD153)....
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...…on the The cellular response to unfolded proteins in the ER protein folding and degradation apparatus in the organ- (UPR) has two known functional components: inhibition elle (Harding et al., 1999; Harding et al., 2000; Sood et of protein synthesis and activation of gene expression. al., 2000a)....
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...HRI attenuates protein synthesis in heme- Two distinct signaling pathways mediated by IRE1a & deficient erythroid precursors, matching hemoglobin b and ATF6 have been implicated in activating gene synthesis with iron availability (Chen and London, 1995). expression, whereas PERK was believed to be responsiIn cells deprived of nutrients, activation of mammalian ble for translational regulation in the UPR (reviewed in GCN2 conserves scarce amino acids for use in essential Kaufman, 1999)....
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...PERK was required for ATF4 accumulation duringexpressed GCN4 mRNA contains several short up- stream open reading frames (uORFs)....
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...In the absence of PERK, cells experimetabolic processes (Berlanga et al., 1999; Sood et al., ence more ER stress and are hypersensitive to its lethal 2000b)....
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