The PERK Signaling
PERK is an important component which is a type I ER transmembrane protein kinase in UPR pathways. Activated PERK subsequently phosphorylate α subunit of eukaryotic translation initiation factor 2 (eIF2α), thereby bringing about the global attenuation of protein translation. Because of the attenuation, all the proteins with a shorter half-life are degraded and cleared from the cell. Since IκB has a much shorter half-life than NF-κB, NF-κB expression is promoted. In addition to that, eIF2α phosphorylation increase the translation of selective mRNA, which is containing inhibitory upstream open reading frames (uORFs) within their 5’ untranslated region (UTR) that prevents translation in unstressed cells[3]. Simultaneously, activating transcription factor 4 (ATF4) escapes this inhibition and preferentially gets translated by altering the translation initiation site. But according to PERK-dependent UPR target genes in mammalian cells, nearly half of the PERK-dependent targets are ATF4-independent. This suggests the existence of other PERK downstream effectors[3]. Subsequently, ATF4 induces the expression of CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP/DDIT3) and growth arrest and DNA damage gene (GADD34). GADD34 is a regulatory subunit of protein phosphatase 1 (PP1) and it acts as a regulator of eIF2α phosphorylation. It directs the PP1 to dephosphorylate eIF2α, acting as an inhibitor[5], [7], [8], [12], [13]. PERK furthermore induces the expression of nuclear factor erythroid 2-related factor 2 (NRF2) which is associated with anti-oxidant stress responses[8], [12]. Figure 2 shows a schematic model of PERK signaling pathway.