Stimulating proteasomal degradation in human proteinopathies.
Maria E Gierisch1, Enrica Barchi1, Nico P Dantuma1
1Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Stockholm, Sweden.
The FEBS Journal
|July 7, 2026
Summary
The ubiquitin-proteasome system (UPS) is a therapeutic target for protein turnover diseases. This review explores strategies to boost UPS function, particularly for neurodegenerative conditions.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- The ubiquitin-proteasome system (UPS) regulates protein degradation and is crucial for cellular health.
- Dysfunctional UPS activity contributes to diseases like cancer and neurodegeneration.
- Targeting UPS offers therapeutic potential, but activators are less developed than inhibitors.
Purpose of the Study:
- To review strategies for enhancing UPS function.
- To highlight the therapeutic potential of UPS activators for proteinopathies.
- To summarize progress in genetic and small-molecule interventions for boosting UPS.
Main Methods:
- Literature review of UPS research.
- Analysis of therapeutic strategies targeting UPS.
- Synthesis of findings on genetic and small-molecule UPS activators.
Main Results:
- Proteasome inhibitors are established cancer therapies.
- Developing UPS activators for neurodegenerative diseases is challenging but promising.
- Various genetic and small-molecule approaches are being investigated to enhance UPS function.
Conclusions:
- Boosting UPS activity is a viable therapeutic strategy for proteinopathies.
- Further research into UPS activators could lead to treatments for neurodegenerative diseases.
- Interventions targeting the UPS hold significant clinical promise across diverse diseases.
Related Concept Videos
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...
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...
02:58Regulated Protein Degradation
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
02:58Regulated Protein Degradation
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
01:17The Proteasome Structure
The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
The proteasome is an...
The proteasome is an...