The unfolded protein response (UPR) is a cellular mechanism that adjusts the endoplasmic reticulum (ER) protein folding capacity in response to stress. The UPR has three branches: IRE1, PERK, and ATF6. These pathways work together to maintain ER homeostasis by reducing misfolded proteins, but can also trigger apoptosis if the stress is not resolved. The study shows that IRE1 signaling is attenuated under persistent ER stress, while PERK signaling remains active. This difference in signaling duration determines whether the cell survives or dies. The researchers used a chemical genetic approach to control IRE1 activity in human cells, demonstrating that prolonged IRE1 signaling enhances cell survival. In models of retinitis pigmentosa, the UPR was shown to contribute to photoreceptor cell death due to misfolded rhodopsin. The findings suggest that the UPR's ability to switch between protective and apoptotic responses is crucial for cell fate decisions. The study highlights the importance of understanding how different UPR branches interact to determine the cell's response to ER stress. The results provide a molecular basis for how cells decide to live or die in response to ER stress.The unfolded protein response (UPR) is a cellular mechanism that adjusts the endoplasmic reticulum (ER) protein folding capacity in response to stress. The UPR has three branches: IRE1, PERK, and ATF6. These pathways work together to maintain ER homeostasis by reducing misfolded proteins, but can also trigger apoptosis if the stress is not resolved. The study shows that IRE1 signaling is attenuated under persistent ER stress, while PERK signaling remains active. This difference in signaling duration determines whether the cell survives or dies. The researchers used a chemical genetic approach to control IRE1 activity in human cells, demonstrating that prolonged IRE1 signaling enhances cell survival. In models of retinitis pigmentosa, the UPR was shown to contribute to photoreceptor cell death due to misfolded rhodopsin. The findings suggest that the UPR's ability to switch between protective and apoptotic responses is crucial for cell fate decisions. The study highlights the importance of understanding how different UPR branches interact to determine the cell's response to ER stress. The results provide a molecular basis for how cells decide to live or die in response to ER stress.