Related Experiment Video
Updated: Jan 21, 2026
05:33
High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
Published on: November 9, 2020
11.0K
Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy
Moran Dvela-Levitt1, Maria Kost-Alimova2, Maheswarareddy Emani1
1Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Cell
|July 27, 2019
Summary
A novel small molecule, BRD4780, clears toxic Mucin 1 kidney disease (MKD) protein aggregates by targeting the TMED9 receptor. This discovery offers a promising therapeutic strategy for MKD and other proteinopathies.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Toxic proteinopathies result from intracellular misfolded protein accumulation, lacking targeted treatments.
- Mucin 1 kidney disease (MKD) is caused by a MUC1 gene frameshift mutation (MUC1-fs), leading to toxic intracellular accumulation.
- The ATF6 unfolded protein response (UPR) pathway is activated by MUC1-fs accumulation.
Purpose of the Study:
- To identify therapeutic strategies for Mucin 1 kidney disease (MKD).
- To investigate the mechanism of MUC1-fs intracellular accumulation and clearance.
- To explore the role of cargo receptors in misfolded protein trafficking.
Main Methods:
- Screening for small molecules that clear MUC1-fs.
- Utilizing patient-derived cells, knockin mouse models, and kidney organoids.
- Investigating the interaction between BRD4780, MUC1-fs, and the TMED9 cargo receptor.
Main Results:
- BRD4780 effectively clears MUC1-fs from patient cells, mouse kidneys, and organoids.
- MUC1-fs is sequestered in TMED9-containing vesicles within the early secretory pathway.
- BRD4780 binds TMED9, releasing MUC1-fs for lysosomal degradation, mimicking TMED9 deletion effects.
Conclusions:
- BRD4780 is a promising therapeutic lead for Mucin 1 kidney disease (MKD).
- The study reveals a novel mechanism of misfolded protein entrapment by cargo receptors.
- Targeting TMED9 offers a strategy for releasing and degrading misfolded proteins in toxic proteinopathies.
Related Concept Videos
02:58Regulated Protein Degradation
8.8K
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...
8.8K
02:58Regulated Protein Degradation
3.1K
3.1K
02:11Proteins: From Genes to Degradation
14.2K
Within a biological system, the DNA encodes the RNA, and the nucleotide sequence in the RNA further defines the amino acid sequence in the protein. This is referred to as “The Central Dogma of Molecular Biology” - a term coined by Francis Crick. Central dogma is a firm principle in biology that defines the flow of genetic information within any life form. The two fundamental steps in central dogma are - transcription and translation.
Transcription is the synthesis of RNA...
Transcription is the synthesis of RNA...
14.2K
01:31Lysosomes
25.4K
Lysosomes are membrane-enclosed spherical sacs derived from the Golgi apparatus. The most important function of the lysosome is degrading macromolecules and biological polymers that are released during membrane trafficking events such as the secretory, endocytic, autophagic, and phagocytic pathways. The degradation is carried out by several hydrolytic enzymes active in an acidic environment of the lysosomal lumen. These acid hydrolases are involved in cellular processes such as cell signaling,...
25.4K
01:45Positive Regulator Molecules
134.6K
To consistently produce healthy cells, the cell cycle—the process that generates daughter cells—must be precisely regulated.
134.6K
01:22Lysosomal Hydrolases
4.5K
Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
4.5K