Pancreatic eukaryotic initiation factor-2 alpha kinase (PEK) homologues inhumans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress
R. Sood et al., Pancreatic eukaryotic initiation factor-2 alpha kinase (PEK) homologues inhumans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress, BIOCHEM J, 346, 2000, pp. 281-293
In response to different cellular stresses, a family of protein kinases reg
ulates translation by phosphorylation of the a:subunit of eukaryotic initia
tion factor-2 (eIF-2 alpha). Recently, we identified a new family member, p
ancreatic eIF-2 alpha kinase (PEK) from rat pancreas. PEK, also referred to
as RNA-dependent protein kinase (PKR)-like endoplasmic reticulum (ER) kina
se (PERK) is a transmembrane protein implicated in translational control in
response to stresses that impair protein folding in the ER. In this study,
we identified and characterized PEK homologues from humans, Drosophila mel
anogaster and Caenorhabditis elegans. Expression of human PEK mRNA was foun
d in over 50 different tissues examined, with highest levels in secretory t
issues. In mammalian cells subjected to ER stress, we found that elevated e
IF-2 alpha phosphorylation was coincident with increased PEK autophosphoryl
ation and eIF-2 alpha kinase activity. Activation of PEK was abolished by d
eletion of PEK N-terminal sequences located in the ER lumen. To address the
role of C. elegans PEK in translational control, we expressed this kinase
in yeast and found that it inhibits growth by hyperphosphorylation of eIF-2
alpha and inhibition of eIF-2B. Furthermore, we found that vaccinia virus
K3L protein, an inhibitor of the eIF-2 alpha kinase PKR involved in an anti
-viral defence pathway, also reduced PEK activity. These results suggest th
at decreased translation initiation by PEK during ER stress may provide the
cell with an opportunity to remedy the folding problem prior to introducin
g newly synthesized proteins into the secretory pathway.