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Endoplasmic reticulum stress signaling in disease
Stefan J Marciniak1, David Ron
1Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. sjm20@cam.ac.uk
Physiological Reviews
|October 4, 2006
Summary
The unfolded protein response (UPR) maintains endoplasmic reticulum homeostasis. UPR dysfunction is implicated in diseases like diabetes, atherosclerosis, and cancer, highlighting its critical role in cellular health.
Area of Science:
- Cellular Biology
- Molecular Biology
- Pathology
Background:
- The endoplasmic reticulum (ER) is crucial for protein maturation, especially for secreted or cell-surface proteins.
- The unfolded protein response (UPR) is a cellular mechanism that balances protein synthesis load with ER capacity.
- ER stress and UPR dysfunction are linked to various human diseases.
Purpose of the Study:
- To review the role of the UPR in human diseases.
- To explore the UPR's involvement in diabetes mellitus, atherosclerosis, and neoplasia.
- To highlight the significance of UPR signaling in disease pathogenesis.
Main Methods:
- Literature review of UPR research.
- Analysis of UPR's role in specific disease contexts.
- Synthesis of current understanding of UPR in disease.
Main Results:
- UPR dysfunction is a key factor in diseases associated with high extracellular protein synthesis.
- The UPR is critical for pancreatic beta-cell function due to insulin synthesis demands.
- UPR involvement extends to peripheral insulin resistance, not just beta-cells.
Conclusions:
- UPR dysfunction contributes significantly to the pathogenesis of diabetes mellitus.
- The UPR's role in disease is broader than previously thought, impacting insulin resistance.
- Understanding UPR mechanisms is vital for developing therapeutic strategies for UPR-related diseases.
Related Concept Videos
01:17Role of ER in the Secretory Pathway
Eukaryotic cells have a special pathway that enables communication between various intracellular membrane-bound compartments and also with the extracellular environment. This pathway is termed as the secretory pathway.
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
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...
01:37The 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...
01:27Post-translational Translocation of Proteins to the RER
A sizable fraction of proteins destined for ER are first synthesized in the cell cytosol and then transported across the ER membrane–a process called post-translational translocation. Similar to cotranslationally translocated proteins, these proteins also use the Sec translocon complex to enter the ER lumen.
Targeting proteins to the ER
Hsp40 and Hsp70 chaperone molecules bind the translated proteins in the cytosol to prevent their folding. The chaperone binding helps to keep the signal...
Targeting proteins to the ER
Hsp40 and Hsp70 chaperone molecules bind the translated proteins in the cytosol to prevent their folding. The chaperone binding helps to keep the signal...
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...
01:34Directing Proteins to the Rough Endoplasmic Reticulum
The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...