Protein misfolding in the endoplasmic reticulum (ER) leads to cell death through PERK-mediated phosphorylation of eIF2α, but the underlying mechanism is not well understood. This study used ChIP-seq and mRNA-seq to identify key transcription factors, ATF4 and CHOP, which interact to directly induce genes encoding protein synthesis and the unfolded protein response, but not apoptosis. Forced expression of ATF4 and CHOP increased protein synthesis and caused ATP depletion, oxidative stress, and cell death. The increased protein synthesis and oxidative stress were necessary for cell death. The results show that eIF2α phosphorylation attenuates protein synthesis, not mRNA translation, to promote cell survival. These findings suggest that limiting protein synthesis may be therapeutic for diseases caused by ER protein misfolding.Protein misfolding in the endoplasmic reticulum (ER) leads to cell death through PERK-mediated phosphorylation of eIF2α, but the underlying mechanism is not well understood. This study used ChIP-seq and mRNA-seq to identify key transcription factors, ATF4 and CHOP, which interact to directly induce genes encoding protein synthesis and the unfolded protein response, but not apoptosis. Forced expression of ATF4 and CHOP increased protein synthesis and caused ATP depletion, oxidative stress, and cell death. The increased protein synthesis and oxidative stress were necessary for cell death. The results show that eIF2α phosphorylation attenuates protein synthesis, not mRNA translation, to promote cell survival. These findings suggest that limiting protein synthesis may be therapeutic for diseases caused by ER protein misfolding.