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.