How Cells Manage Protein Stress by Linking the Protein Folding Response with Other Stress Systems

The endoplasmic reticulum (ER) plays a crucial role in cellular proteostasis, coordinating various cellular functions.

• Disruptions in ER function activate the unfolded protein response (UPR), involving key signaling proteins PERK, IRE1α, and ATF6.
• The UPR is increasingly recognized as a central coordinator of various cellular stress-response pathways rather than just a stress-mitigating mechanism.
• Transient activation of the UPR may promote cellular adaptation through coordinated responses across transcription, translation, and organelle functions.
• Sustained or unresolved ER stress could lead to maladaptive outcomes, including mitochondrial dysfunction, dysregulated autophagy, oxidative imbalance, and apoptosis.
• The UPR interacts with multiple stress pathways, linking ER proteostasis to cell fate decisions during stress.

Simplified