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A chemical genetics approach to study the Integrated Stress Response reveals common and new signaling mechanisms


Maintaining homeostasis is vital for biological systems. To maintain homeostasis, cells rely on specialized complex mechanisms, known as cell stress responses, that detect specific internal imbalances and react to them. 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 has two faces, 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 a common, cell-autonomous apoptosis mechanism that requires unconventional signaling by death receptor 5. We also show that the ISR selectively activates the endoplasmic reticulum (ER) stress sensor IRE1 in the absence of ER stress. Together, our results indicate that a common ISR mechanism eliminates terminally injured cells and reveal a new level of intercommunication between the ISR and other stress responses.

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