The integrated stress response (ISR) is a fundamental signaling network that leverages the cell's biosynthetic capacity against different stresses to restore homeostasis. However, when homeostasis is unattainable, the ISR switches to drive cell death and eliminate irreparably damaged cells. Previous work has shown that persistent activity of the ISR kinase PERK during unyielding endoplasmic reticulum (ER) stress induces apoptosis downstream of death receptor 5 (DR5) [1]. ER stress provides activating signals that engage the ectodomain (ED) of DR5 to drive its unconventional activation in the Golgi apparatus [1, 2]. Here, using chemical genetics to uncouple stress sensing from ISR activation, we found that DR5 signaling from the Golgi apparatus is integral to the ISR and not specific to ER stress. Furthermore, we show that DR5 activation can be driven solely by increased expression and does not require its ED. These findings indicate that a general ISR kill switch eliminates irreversibly injured cells.