Nonstandard abbreviations used: endoplasmic reticulum (ER); unfolded protein response (UPR); integrated stress response (ISR); upstream open reading frame (uORF). their related lumenal domains. Under conditions of ER stress, BiP partitions to service the increasing load of ER client proteins; loss of BiP binding correlates with oligomerization, trans-autophosphorylation, and activation of downstream signaling by PERK (and IRE1)(15, 16). This model for PERK activation explains the coupling between folding capacity in the ER lumen and polypeptide biosynthesis on the other side of the membrane. As long as there is dispensable BiP to bind and inactivate PERK, translation and translocation of client proteins continue apace. However, when folding capacity of the ER is exceeded, PERK is activated, eIF2α is phosphorylated, and protein synthesis and client protein translocation into the ER lumen are attenuated. PERK is both necessary and sufficient for this regulation, as activated PERK directly phosphorylates eIF2α, and Perk–/–cells lose ability to control translation in response to ER stress (17). Furthermore, PERK activation, eIF2α phosphorylation, and inhibition of protein synthesis occur within minutes following the development of ER stress (13, 17). By contrast, the activation of UPR target genes does not begin until 1–2 hours later. Thus, PERK activation and translational control are likely to be the first line of defense against ER stress. In the experimental systems used to study the UPR, PERK-mediated translational repression is global, affecting the translation of both cytoplasmic and ER client proteins. It is possible, however, that in physiological conditions and with more moderate levels of stress, PERK selectively targets a pool of eIF2α that services initiation on ER-associated ribosomes. Loss of PERK activity has severe consequences for the ability of cells to resist ER stress. Perk–/–cells are hypersensitive to the lethal affects of toxins like tunicamycin and thapsigargin that cause ER stress by perturbing the folding of ER client proteins. This increased susceptibility to agents that cause ER stress correlates with the observation that the parallel IRE1 pathway is hyperactive in Perk–/–cells, an indication that these cells experience more ER stress (17). While the mediators of death in ER-stressed Perk–/–cells are not known, these cells experience more activation of caspase-12 (17), which has been implicated in this apoptotic response (18). The only known substrates of PERK’s kinase activity are PERK itself and eIF2α. The phenotype of cells in which eIF2α has been rendered incapable of undergoing phosphorylation by PERK (eIF2αS51A knock-in cells) suggests that from the perspective of hypersensitivity to ER stress, both genes function in a linear pathway (19). Furthermore, the hypersensitivity of Perk–/–cells to ER stress can also be partially rescued by inhibiting protein synthesis (17). Together, these findings suggest that loss of translational control and the resulting inability to match client protein load to folding capacity render cells hypersensitive to ER stress.