Related Experiment Video
Updated: May 8, 2026
10:12
Measuring Endoplasmic Reticulum Stress and Unfolded Protein Response in HIV-1 Infected T-Cells and Analyzing its Role in HIV-1 Replication
Published on: June 14, 2024
Targeting the unfolded protein response in disease
Claudio Hetz1, Eric Chevet, Heather P Harding
11] Biomedical Neuroscience Institute, Program of Cellular and Molecular Biology, ICBM, Faculty of Medicine, University of Chile, 1027 Independencia, PO Box 70086, Santiago, Chile. [2] Department of Immunology and Infectious Diseases, Harvard School of Public Health, 651 Huntington Avenue, Boston, Massachusetts 02115, USA.
Nature Reviews. Drug Discovery
|August 31, 2013
Summary
Endoplasmic reticulum (ER) stress from unfolded proteins is implicated in many diseases. Novel compounds and therapies aim to manage ER stress, offering new treatment strategies for conditions like cancer and neurodegeneration.
Area of Science:
- Molecular biology
- Cellular stress response
- Disease pathogenesis
Background:
- Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes cellular stress.
- This ER stress is a hallmark of specialized secretory cells and various diseases, including cancer, diabetes, obesity, and neurodegenerative disorders.
- The unfolded protein response (UPR) is a cellular adaptation pathway to manage ER stress.
Purpose of the Study:
- To review recent advancements in therapeutic strategies targeting ER stress.
- To discuss novel compounds designed to modulate ER stress levels in disease.
Main Methods:
- Literature review of recent research on ER stress and UPR.
- Analysis of emerging therapeutic compounds and strategies.
- Discussion of the role of ER stress in disease pathology.
Main Results:
- ER stress is a critical factor in the progression of numerous diseases.
- The UPR is a key cellular mechanism for adapting to ER stress.
- Failure of adaptation mechanisms leads to apoptosis.
- Novel therapeutic approaches are being developed to target ER stress.
Conclusions:
- Manipulating ER stress represents a promising therapeutic avenue for various diseases.
- Further research into novel compounds and strategies is crucial for clinical translation.
- Understanding the UPR is key to developing effective treatments for ER stress-related disorders.
Related Concept Videos
01:37The Unfolded Protein Response
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
01:31Regulation of the Unfolded Protein Response
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
01:13The Proteasome
Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin...
02:18The Proteasome
Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
01:29Protein Folding Quality Check in the RER
ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
01:32Export of Misfolded Proteins out of the ER
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...