Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 230

Important modulators of cell metabolism also regulate the IRE1α
pathway. It was recently described that both XBP1 splicing and JNK
activation are controlled by the mTORC1 pathway, the major sensor of
nutrient and energy availability in the cell ( Ozcan et al., 2008 ; Pfaffen-
bach et al., 2010 ; Kato et al., 2012). IRE1α is phosphorylated by PKA,
controlling glucagon-mediated expression of gluconeogenic genes ( Mao
et al., 2011 ). p85, a repressive regulatory subunit of PI3K, also inter-
acts with XBP1, increasing its nuclear translocation and transcriptional
activity ( Park et al., 2010 ). IRE1α signaling is attenuated after prolonged
ER stress and this process is characterized by IRE1α cluster dissolution,
IRE1α dephosphorylation and a decline in endoribonuclease activity ( Li
et al., 2010 ; Rubio et al., 2011 ). Additionally, the E3 ubiquitin ligase
synoviolin increases IRE1α ubiquitination and degradation in synovial
fibroblasts ( Gao et al., 2008 ).
3.2.2. PERK Pathway
The second ER stress transducer is PERK, first described in mamma-
lian pancreatic islet cells by Shi et al. This protein has a PEK-like catalytic
domain, which phosphorylates the α subunit of the eukaryotic translation
initiation factor-2 (eIF2α) ( Shi et al., 1998 ). PERK possesses a luminal
domain similar to that of IRE1, and a cytoplasmic portion that manifests
protein serine/threonine kinase activity. As such, PERK is a member of the
eIF2α kinase subfamily together with PKR, GCN2 and HRI ( Harding
et al., 1999 ). PERK is conserved in all known metazoans, but is absent in
the S. cerevisiae genome. In Drosophila melanogaster , its homolog is DPERK
( Pomar et al., 2003 ).
As mentioned, PERK is a type I transmembrane protein with a typi-
cal protein kinase structure that includes a large C-terminal lobe and a
smaller N-terminal lobe linked by a short hinge loop. The C-terminal lobe
is formed by a large activation loop, seven α-helices and two short β-strands.
The N-terminal lobe contains three α-helices and five β-strands. A phos-
phate moiety was found in the electron density map at the position Thr980,
and phosphorylation at this site is thought to stabilize the activation loop
and the eIF2α-binding site in the αG helix ( Cui et al., 2011 ).
When the UPR has not been activated, BiP/GRP78 is bound to the
PERK luminal domain. Upon unfolded protein accumulation, BiP/GRP78
dissociates from PERK, and the loss of this interaction correlates with the
formation of high molecular mass complexes of activated PERK. BiP/
GRP78 overexpression attenuates this activation ( Bertolotti et al., 2000 ).