The integrated stress response induces a common cell-autonomous death receptor 5-dependent apoptosis switch

The integrated stress response (ISR) is a fundamental signaling network that reprograms the transcriptome and proteome to leverage the cell’s biosynthetic capacity against different stresses. Signaling plasticity is enabled by distinct ISR sensor kinases that detect specific perturbations. The ISR is dichotomous, with tailored homeostatic outputs and a terminal one engaged upon overwhelming stress. Through a chemical-genetics approach that uncouples natural stress inputs from ISR actuation, we show that the ISR engages an input-agnostic, cell-autonomous apoptosis mechanism that requires unconventional signaling by death receptor 5. Our results indicate that a common ISR mechanism eliminates terminally injured cells.