Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 231

ER stress leads to an increase in PERK's protein kinase activity and eIF2α
phosphorylation, which competitively binds to eIF2β, a guanine nucleotide-
exchange factor. This results in eIF2α-GDP to eIF2α-GTP exchange inhi-
bition, the latter being a key component in the formation of the active 43S
translation-initiation complex ( Dever, 2002 ). Therefore, the PERK pathway
inhibits general mRNA translation, decreasing global protein synthesis and
reducing the ER load. PERK also contributes to UPR transcriptional acti-
vation and in ER-stressed PERK knockout cells, a characteristic decrease
in mRNA responsible for normal UPR is observed ( Harding et al., 2003 ).
Gene expression in response to eIF2α phosphorylation is conserved
among eukaryotes. The transcription factor ATF4 is translationally induced
because it has an upstream open reading frame (ORF) in its 5′-untranslated
region. This upstream ORF, which under normal conditions, prevents trans-
lation of the true ATF4, is bypassed only when eIF2α is phosphorylated, and
therefore, ATF4 translation occurs ( Harding et al., 2000 ). One favored gene
during this process is gadd153, also known as chop , an ER stress-induced
proapoptotic factor ( Fawcett et al., 1999 ). Also, the Nrf2 transcription fac-
tor is a substrate of PERK. In unstressed cells, Nrf2 is maintained in the
cytoplasm by its association with Keap1. PERK-mediated phosphorylation
triggers dissociation of Nrf2/Keap1 complexes and inhibits their reassocia-
tion, consequently causing Nrf2 nuclear import ( Cullinan et al., 2003 ).
The entire range of PERK-dependent gene expression relies on eIF2α
phosphorylation in Ser51, which is blocked in the Ser51Ala eIF2α mutant
( Lu et al., 2004 ). In addition to its role in the ER stress, PERK plays an
important role in activation of autophagy as a survival mechanism during
episodes of nutrient deprivation, hypoxia and radiation ( Ogata et al., 2006 ;
Rouschop et al., 2010 ; Rzymski et al., 2010 ). These two functions allow
PERK to regulate growth and survival ( Bi et al., 2005 ; Blais et al., 2006 ).
After restoring homeostasis, activated PERK is dephosphorylated ( Ber-
tolotti et al., 2000 ) by mechanisms that remain to be determined. Also,
active eIF2α is dephosphorylated by two phosphatases that function inde-
pendently, namely CReP, a constitutively expressed phosphatase ( Jousse
et al., 2003 ), and GADD34, whose expression is induced by phosphorylated
eIF2α ( Novoa et al., 2001 ). A HSP40 family member, P58(IPK), also regu-
lates PERK by binding to the kinase domain of the sensor and decreasing
eIF2α phosphorylation. This regulation affects the expression of its down-
stream targets, decreasing the translation of the UPR target proteins BiP
and CHOP. Moreover, P58(IPK) has also been implicated in the inhibition
of PERK autophosphorylation ( Yan et al., 2002 ).