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

Abstract

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.

Signaling plasticity in the integrated stress response

“…In the ER, unfolded proteins activate PERK, as well as IRE1, and ATF6, two key ER stress sensors. PERK induces the phosphatase RPAP2, which dephosphorylates IRE1 (Chang et al, 2018), establishing negative feedback control to suppress IRE1 pro-survival signals and favor PERK-dependent apoptosis (Chang et al, 2018;Muniozguren et al, 2022). Similarly, ER stress induces BiP downstream of ATF6 and IRE1, thereby exerting negative feedback control of PERK-and IRE1 and ATF6-activities to resolve ER stress (Wang et al, 2000).…”