The aftermath of the interplay between the endoplasmic reticulum stress response and redox signaling

The endoplasmic reticulum (ER) is an essential organelle of eukaryotic cells. Its main functions include protein synthesis, proper protein folding, protein modification, and the transportation of synthesized proteins. Any perturbations in ER function, such as increased demand for protein folding or the accumulation of unfolded or misfolded proteins in the ER lumen, lead to a stress response called the unfolded protein response (UPR). The primary aim of the UPR is to restore cellular homeostasis; however, it triggers apoptotic signaling during prolonged stress. The core mechanisms of the ER stress response, the failure to respond to cellular stress, and the final fate of the cell are not yet clear. Here, we discuss cellular fate during ER stress, cross talk between the ER and mitochondria and its significance, and conditions that can trigger ER stress response failure. We also describe how the redox environment affects the ER stress response, and vice versa, and the aftermath of the ER stress response, integrating a discussion on redox imbalance-induced ER stress response failure progressing to cell death and dynamic pathophysiological changes. Cell biology: Protein misfolding induces vicious cycle of cellular stress The endoplasmic reticulum (ER), a cellular organelle responsible for protein folding, is sensitive to chemical imbalances that can induce stress, leading to cell death and disease. Researchers in South Korea, led by Han-Jung Chae from Jeonbuk National University in Jeonju and Hyung-Ryong Kim from Dankook University in Cheonan, review how the ER counters changes in its environment that spur protein folding defects by activating a series of signaling pathways, known collectively as the unfolded protein response. Redox imbalance, may fail adaptive ER stress response that can damage the ER and surrounding mitochondria by modifying cysteine residues. The interaction between the two stress systems, ER stress and oxidative stress, has profound negative impacts on normal physiology. Targeting one or both of these stress mechanisms may therefore be an effective means of treating disease.

Automated summary

The endoplasmic reticulum (ER) plays crucial roles in protein synthesis and folding in eukaryotic cells. The unfolded protein response (UPR) is triggered by disturbances in ER function, aiming to restore cellular homeostasis but possibly leading to apoptotic signaling under prolonged stress. The complex interactions between ER stress, redox imbalance, and oxidative stress can have profound negative impacts on cellular physiology and targeting these stress mechanisms may be a promising approach for disease treatment.