Related Experiment Video
Updated: Dec 17, 2025
10:56
Assays for the Degradation of Misfolded Proteins in Cells
Published on: August 28, 2016
12.4K
Nonsense-mediated mRNA decay factor UPF1 promotes aggresome formation
Yeonkyoung Park1,2, Joori Park1,2, Hyun Jung Hwang1,2
1Creative Research Initiatives Center for Molecular Biology of Translation, Korea University, Seoul, 02841, Republic of Korea.
Nature Communications
|June 21, 2020
Summary
Nonsense-mediated mRNA decay (NMD) byproducts, truncated polypeptides, accumulate in aggresomes when protein degradation is overwhelmed. UPF1 hyperphosphorylation targets these aggregates for clearance, suppressing stress-induced apoptosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Nonsense-mediated mRNA decay (NMD) is a crucial mRNA surveillance pathway.
- NMD can generate truncated, misfolded polypeptides as byproducts.
- The ubiquitin-proteasome system (UPS) degrades misfolded proteins, but can be overwhelmed.
Purpose of the Study:
- To investigate the fate of NMD-generated polypeptides when the UPS is overwhelmed.
- To elucidate the role of UPF1 in the cellular response to proteotoxic stress.
- To understand the mechanism of aggresome targeting and clearance.
Main Methods:
- Cellular assays to monitor polypeptide accumulation and degradation.
- Biochemical analysis of UPF1 phosphorylation and its interaction with cellular machinery.
- Single-particle tracking to visualize aggregate movement.
- Apoptosis assays under proteotoxic stress conditions.
Main Results:
- Misfolded polypeptides, including NMD-polypeptides, accumulate in aggresomes when the UPS is overwhelmed.
- UPF1 hyperphosphorylation is essential for targeting these aggregates to aggresomes via the CTIF-eEF1A1-DCTN1 complex.
- UPF1 enhances the efficiency and accuracy of aggregate transport to aggresomes.
- UPF1 hyperphosphorylation suppresses apoptosis induced by proteotoxic stress.
Conclusions:
- UPF1 plays a dual role in both mRNA quality control and protein surveillance.
- Hyperphosphorylated UPF1 acts as a key regulator in the aggresome pathway, managing misfolded protein aggregates.
- This pathway is critical for cellular survival under proteotoxic stress.
More Related Videos
Related Concept Videos
02:27Nonsense-mediated mRNA Decay
11.5K
The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
11.5K
02:27Nonsense-mediated mRNA Decay
3.2K
3.2K
02:31Nuclear Export of mRNA
8.5K
Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
8.5K
02:51mRNA Stability and Gene Expression
6.3K
The structure and stability of mRNA molecules regulates gene expression, as mRNAs are a key step in the pathway from gene to protein. In eukaryotes, the half-life of mRNA varies from a few minutes up to several days. mRNA stability is essential in growth and development. The absence of the proteins regulating its stability, such as tristetraprolin in mice, can cause systemic issues, including bone marrow overgrowth, inflammation, and autoimmunity.
Cis-acting Elements involved in mRNA stability
Cis-acting Elements involved in mRNA stability
6.3K
02:51mRNA Stability and Gene Expression
3.3K
3.3K
01:37The Unfolded Protein Response
6.1K
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...
6.1K