Hp. Harding et al., Perk is essential for translational regulation and cell survival during the unfolded protein response, MOL CELL, 5(5), 2000, pp. 897-904
Malfolded proteins in the endoplasmic reticulum (ER) inhibit translation in
itiation. This response is believed to be mediated by increased phosphoryla
tion of eukaryotic initiation factor 2 alpha (eIF2 alpha) and is hypothesiz
ed to reduce the work load imposed on the folding machinery during stress.
Here we report that mutating the gene encoding the ER stress-activated eIF2
alpha kinase PERK abolishes the phosphorylation of eIF2 alpha in response
to accumulation of malfolded proteins in the ER resulting in abnormally ele
vated protein synthesis and higher levels of ER stress. Mutant cells are ma
rkedly impaired in their ability to survive ER stress and inhibition of pro
tein synthesis by cycloheximide treatment during ER stress ameliorates this
impairment. PERK thus plays a major role in the ability of cells to adapt
to ER stress.