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Targeting endoplasmic reticulum stress in metabolic disease
Stewart Siyan Cao1, Randal J Kaufman
1Del E. Webb Neuroscience, Aging and Stem Cell Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Expert Opinion on Therapeutic Targets
|January 18, 2013
Summary
Endoplasmic reticulum (ER) stress impacts protein folding and is linked to metabolic diseases. Targeting ER stress with pharmacological modulators shows therapeutic promise for conditions like type 2 diabetes and obesity.
Area of Science:
- Cellular Biology
- Metabolic Disease Research
- Pharmacology
Background:
- Endoplasmic reticulum (ER) stress disrupts cellular protein folding homeostasis.
- ER stress is implicated in the pathogenesis of various metabolic disorders.
- Pharmacological ER stress modulators show potential for treating metabolic diseases.
Purpose of the Study:
- To review the molecular mechanisms of ER stress and the unfolded protein response (UPR) in metabolic diseases.
- To highlight the role of UPR components in disease models.
- To emphasize the therapeutic potential of small molecules targeting ER stress.
Main Methods:
- Review of molecular mechanisms of ER stress and UPR.
- Analysis of UPR component roles in mouse disease models.
- Focus on small molecule efficacy in animal models and human pathologies.
Main Results:
- ER stress is a significant factor in metabolic disease development.
- Small molecular chemical chaperones have shown efficacy in preclinical and clinical studies.
- Targeting specific UPR pathways offers new therapeutic avenues.
Conclusions:
- ER stress represents a promising therapeutic target for metabolic diseases.
- Small molecules, including chemical chaperones, demonstrate therapeutic benefits.
- Further research is needed to confirm efficacy and safety for human use.
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...
01:21Smooth Endoplasmic Reticulum
Smooth endoplasmic reticulum or smooth ER is a sub-organelle with specialized functions in animal cells and plant cells. It is often associated with the tubule morphology of the endoplasmic reticulum.
The ER provides optimal conditions for synthesizing steroid hormones and lipids, such as phospholipids and triglycerides. Traditionally, lipid metabolism was considered to be a smooth ER function. However, there is no direct evidence to prove that rough ER is completely excluded from lipid...
The ER provides optimal conditions for synthesizing steroid hormones and lipids, such as phospholipids and triglycerides. Traditionally, lipid metabolism was considered to be a smooth ER function. However, there is no direct evidence to prove that rough ER is completely excluded from lipid...
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...
01:32Export 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...
01:37The 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...