The article discusses the role of translational control in the endoplasmic reticulum (ER) stress response. The ER is a critical organelle for folding and posttranslational modification of proteins, and its capacity to handle the load of client proteins is regulated by the unfolded protein response (UPR). When the ER faces stress, characterized by an imbalance between the load of client proteins and the organelle's folding capacity, specific signaling pathways and effector mechanisms are activated to manage this stress. The first component of the ER stress response is the upregulation of ER chaperones, enzymes, and structural components to enhance the ER's capacity. The second component involves the repression of protein biosynthesis through the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which inhibits the initiation step in polypeptide biosynthesis. The third component is programmed cell death, which is less well-understood but plays a crucial role in the adaptive response to ER stress. The article highlights the role of PERK, a kinase that links ER stress to eIF2α phosphorylation. PERK is activated under conditions of ER stress, leading to the phosphorylation of eIF2α and the inhibition of protein synthesis. This process is rapid and occurs within minutes, making it the first line of defense against ER stress. Loss of PERK activity leads to severe hypersensitivity to ER stress, as seen in Perk knockout mice, which develop diabetes mellitus and bone defects due to the destruction of pancreatic β cells and osteoblasts. The article also explores the physiological roles of PERK, such as its involvement in modulating protein biosynthesis in response to physiological levels of ER stress. It discusses the similarities between PERK and another eIF2α kinase, HRI, in preventing proteotoxicity. The integrated stress response (ISR) is proposed to integrate different stress signals and regulate gene expression, including the transcription of stress-induced genes like CHOP. The ISR may also play a role in translational recovery during stress, as suggested by the identification of GADD34, a target gene of the ISR, which encodes a regulatory subunit of protein phosphatase 1 that dephosphorylates eIF2α. Finally, the article touches on the role of the ISR in apoptosis, noting that while the ISR primarily promotes cell survival, it also has targets that are implicated in programmed cell death. The overall impact of the ISR on cellular homeostasis and stress resistance is discussed, emphasizing its potential broad role in life and death decisions in stressed cells.The article discusses the role of translational control in the endoplasmic reticulum (ER) stress response. The ER is a critical organelle for folding and posttranslational modification of proteins, and its capacity to handle the load of client proteins is regulated by the unfolded protein response (UPR). When the ER faces stress, characterized by an imbalance between the load of client proteins and the organelle's folding capacity, specific signaling pathways and effector mechanisms are activated to manage this stress. The first component of the ER stress response is the upregulation of ER chaperones, enzymes, and structural components to enhance the ER's capacity. The second component involves the repression of protein biosynthesis through the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which inhibits the initiation step in polypeptide biosynthesis. The third component is programmed cell death, which is less well-understood but plays a crucial role in the adaptive response to ER stress. The article highlights the role of PERK, a kinase that links ER stress to eIF2α phosphorylation. PERK is activated under conditions of ER stress, leading to the phosphorylation of eIF2α and the inhibition of protein synthesis. This process is rapid and occurs within minutes, making it the first line of defense against ER stress. Loss of PERK activity leads to severe hypersensitivity to ER stress, as seen in Perk knockout mice, which develop diabetes mellitus and bone defects due to the destruction of pancreatic β cells and osteoblasts. The article also explores the physiological roles of PERK, such as its involvement in modulating protein biosynthesis in response to physiological levels of ER stress. It discusses the similarities between PERK and another eIF2α kinase, HRI, in preventing proteotoxicity. The integrated stress response (ISR) is proposed to integrate different stress signals and regulate gene expression, including the transcription of stress-induced genes like CHOP. The ISR may also play a role in translational recovery during stress, as suggested by the identification of GADD34, a target gene of the ISR, which encodes a regulatory subunit of protein phosphatase 1 that dephosphorylates eIF2α. Finally, the article touches on the role of the ISR in apoptosis, noting that while the ISR primarily promotes cell survival, it also has targets that are implicated in programmed cell death. The overall impact of the ISR on cellular homeostasis and stress resistance is discussed, emphasizing its potential broad role in life and death decisions in stressed cells.