Related Experiment Video
Updated: May 10, 2026
09:47
Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates
Published on: May 10, 2022
Endoplasmic reticulum (ER) ubiquitin ligases: substrate recognition and emerging cellular functions
Qing Zhao1, Zai-Rong Zhang2, Yihong Ye3
1School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
Trends in Cell Biology
|May 8, 2026
Summary
Endoplasmic reticulum (ER) ubiquitin ligases maintain cell balance by degrading misfolded proteins and regulating functional ER proteins. These enzymes are crucial for ER homeostasis and immune responses, with dysregulation linked to neurodegenerative and immune disorders.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- Endoplasmic reticulum (ER)-resident ubiquitin ligases are vital for cellular homeostasis.
- They play key roles in protein quality control, lipid metabolism, innate immunity, and interorganelle communication.
- Beyond degrading misfolded proteins via ER-associated degradation (ERAD), they also regulate functional ER proteins and contribute to ER-phagy.
Purpose of the Study:
- To review recent advances in understanding substrate recognition mechanisms of ER ubiquitin ligases.
- To explore how these enzymes coordinate ER-associated degradation (ERAD) and ER-phagy.
- To discuss their roles in ER homeostasis, immune responses, and disease pathogenesis.
Main Methods:
- Literature review of recent scientific publications.
- Focus on mammalian systems.
- Synthesis of findings on substrate recognition, ERAD, and ER-phagy coordination.
Main Results:
- ER ubiquitin ligases employ diverse substrate recognition mechanisms.
- These enzymes coordinate ERAD and ER-phagy for ER homeostasis.
- Dysregulation of ER ubiquitin ligases is implicated in diseases like neurodegeneration and immune disorders.
Conclusions:
- ER ubiquitin ligases are critical regulators of ER homeostasis through both ERAD and ER-phagy.
- Understanding their substrate recognition is key to elucidating their multifaceted roles.
- Targeting these ligases may offer therapeutic strategies for related diseases.
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...
01:45ER 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...
01:39Endoplasmic Reticulum
The Endoplasmic Reticulum (ER) in eukaryotic cells is a substantial network of interconnected membranes with diverse functions, from calcium storage to biomolecule synthesis. A primary component of the endomembrane system, the ER manufactures phospholipids critical for membrane function throughout the cell. Additionally, the two distinct regions of the ER specialize in the manufacture of specific lipids and proteins.
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...
01:43The Endoplasmic Reticulum
The endoplasmic reticulum or ER makes up for more than half of the membranes in a cell and accounts for 10% of total cell volume. It is also the primary protein and lipid synthesis factory for most cell organelles, such as the Golgi apparatus, lysosomes, secretory vesicles, and the plasma membrane. Despite being the most extensive and functionally complex subcellular organelle, ER was the last to be discovered. After years of deliberation, Keith Porter and George Palade in the year 1954,...
01:43The Endoplasmic Reticulum
The endoplasmic reticulum or ER makes up for more than half of the membranes in a cell and accounts for 10% of total cell volume. It is also the primary protein and lipid synthesis factory for most cell organelles, such as the Golgi apparatus, lysosomes, secretory vesicles, and the plasma membrane. Despite being the most extensive and functionally complex subcellular organelle, ER was the last to be discovered. After years of deliberation, Keith Porter and George Palade in the year 1954,...