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Biology Articles » Biochemistry » Signaling the Unfolded Protein Response from the Endoplasmic Reticulum » UPR Signaling Mediated by PERK

UPR Signaling Mediated by PERK
- Signaling the Unfolded Protein Response from the Endoplasmic Reticulum

 

The most immediate response to ER stress is transient attenuation of mRNA translation by increased phosphorylation of eIF2a (31). When eIF2a is phosphorylated, the formation of the ternary translation initiation complex eIF2-GTP-tRNAMeti is prevented, leading to attenuation of translation in general. The ER-resident kinase PERK is activated in response to ER stress to phosphorylate eIF2a on Ser-51, thereby attenuating protein synthesis to reduce the workload of the ER (3234) (Fig. 3). Murine cells deleted in PERK or mutated at Ser-51 in eIF2a to prevent phosphorylation did not attenuate protein synthesis upon ER stress. As a consequence, these cells were not able to survive ER stress (32). However, it was surprising that the increased ER stress-induced apoptosis in these cells was due to defective transcriptional activation of UPR genes required for adaptation. Whereas phosphorylation of eIF2a by PERK leads to attenuation of global mRNA translation, phosphorylated eIF2a selectively stimulates translation of a specific subset of mRNAs in response to stress (Fig. 3). In yeast, the phosphorylation of eIF2a upon amino acid starvation promotes translation of GCN4 mRNA that encodes a b-ZIP transcription factor required for induction of genes encoding amino acid biosynthetic functions (35). GCN4 mRNA contains multiple upstream open reading frames in its 5'-untranslated receptor. These upstream ORFs, which ordinarily prevent translation of the authentic GCN4 ORF, are bypassed only when eIF2a is phosphorylated, thus allowing translation of the GCN4 ORF (31). This control mechanism is also utilized in mammalian cells to regulate gene expression in response to ER stress and amino acid starvation. For example, upon ER stress, phosphorylated eIF2a selectively promotes translation of ATF4 mRNA (34). ATF4 subsequently activates transcription of genes involved in amino acid metabolism and transport, oxidation-reduction reactions, and ER stress-induced apoptosis (32, 36, 37).



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