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Purification of the Membrane Compartment for Endoplasmic Reticulum-associated Degradation of Exogenous Antigens in Cross-presentation
Published on: August 21, 2017
One step at a time: endoplasmic reticulum-associated degradation
Shruthi S Vembar1, Jeffrey L Brodsky
1Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Nature Reviews. Molecular Cell Biology
|November 13, 2008
Summary
The endoplasmic reticulum-associated degradation (ERAD) pathway degrades misfolded proteins via cytoplasmic proteasomes. This review details ERAD mechanisms and disease relevance.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Protein folding in the endoplasmic reticulum (ER) is regulated by ER quality control (ERQC).
- ERQC directs proteins passing criteria through the secretory pathway.
- Misfolded or unassembled proteins are targeted for degradation by the ER-associated degradation (ERAD) pathway.
Purpose of the Study:
- To summarize the current understanding of the ER-associated degradation (ERAD) pathway.
- To emphasize the factors involved in catalyzing distinct ERAD activities.
- To highlight the importance of ERAD in relation to diseases associated with its substrates.
Main Methods:
- Review of existing literature on ERAD.
- Analysis of molecular chaperones and associated factors in ERAD.
- Emphasis on substrate recognition, retrotranslocation, and degradation.
Main Results:
- ERAD involves recognition and targeting of substrates by chaperones and factors.
- Substrates undergo retrotranslocation from the ER to the cytoplasm.
- Cytoplasmic degradation is carried out by the ubiquitin-proteasome system.
Conclusions:
- ERAD is a critical pathway for maintaining ER homeostasis.
- Dysfunction in ERAD is linked to various human diseases.
- Understanding ERAD factors is key to elucidating disease mechanisms.
Related Concept Videos
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...
01:45ER Retrieval Pathway
In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
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...
01:27Post-translational Translocation of Proteins to the RER
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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
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02:18The Proteasome
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