Related Experiment Video
Updated: May 30, 2025
11:05
Analysis of Endocytic Uptake and Retrograde Transport to the Trans-Golgi Network Using Functionalized Nanobodies in Cultured Cells
Published on: February 21, 2019
9.0K
γ-secretase facilitates retromer-mediated retrograde transport
Yuka Takeo1, Mac Crite1, Kashif Mehmood1
1Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA.
Journal of Cell Science
|January 27, 2025
Summary
The interaction between retromer and γ-secretase is crucial for retrograde protein transport. Inhibiting γ-secretase impairs the trafficking of specific cellular cargoes via retromer-mediated pathways.
Area of Science:
- Cell Biology
- Molecular Biology
- Protein Trafficking
Background:
- Retromer facilitates retrograde transport from endosomes to the trans-Golgi network (TGN).
- γ-secretase is a protease involved in cleaving transmembrane proteins.
- The functional significance of the retromer-γ-secretase complex is currently unknown.
Purpose of the Study:
- To investigate the functional consequences of the interaction between retromer and γ-secretase.
- To determine the role of γ-secretase in retromer-mediated retrograde protein trafficking.
Main Methods:
- Utilized γ-secretase inhibitor XXI and PS1 knockout in cultured human epithelial cells.
- Assessed the endosome-to-TGN trafficking of various retromer-dependent and independent cargoes.
- Examined the association of γ-secretase with retromer cargoes.
Main Results:
- γ-secretase inhibition or PS1 knockout impaired retromer-mediated trafficking of specific cargoes (DMT1-II, CI-M6PR, Shiga toxin).
- Trafficking of retromer-independent cargoes (cholera toxin, mutant CI-M6PR) remained unaffected.
- γ-secretase associates with retromer cargoes independently of retromer, and inhibition did not disrupt these associations or retromer expression.
Conclusions:
- The interaction between γ-secretase and retromer facilitates retromer-mediated retrograde trafficking of cellular transmembrane proteins.
- γ-secretase activity is essential for the efficient retrograde transport of specific protein cargoes.
- This study elucidates a novel role for γ-secretase in protein trafficking pathways regulated by retromer.
Related Concept Videos
01:32Export of Misfolded Proteins out of the ER
3.5K
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...
3.5K
01:45ER Retrieval Pathway
3.8K
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...
3.8K
00:58Recycling Endosomes and Transcytosis
2.6K
The recycling endosome, also known as the endosomal recycling compartment (ERC), is a part of the slow-recycling process of the endocytic pathway. Molecules internalized through receptor-mediated endocytosis are either degraded in the lysosomes or are recycled to the plasma membrane through the fast- or slow-recycling route.
The recycling endosome is not a single organelle but an extensively tubulated network of recycling pathways. It functions in storing molecules or transporting them across...
The recycling endosome is not a single organelle but an extensively tubulated network of recycling pathways. It functions in storing molecules or transporting them across...
2.6K
01:29Insertion of Multi-pass Transmembrane Proteins in the RER
7.8K
The rough ER membrane synthesizes, assembles, and embeds transmembrane proteins in diverse topologies. These proteins function as transporters or channels and can remain in the ER membrane or are sent to the Golgi complex, lysosome, and cell membrane.
The multipass transmembrane proteins are the type IV integral membrane proteins with multiple topogenic sequences determining their spatial arrangement in the ER membrane. Nearly all multipass proteins lack a cleavable signal sequence and use...
The multipass transmembrane proteins are the type IV integral membrane proteins with multiple topogenic sequences determining their spatial arrangement in the ER membrane. Nearly all multipass proteins lack a cleavable signal sequence and use...
7.8K
01:25Rab Cascades
2.6K
Rab GTPases act in a regulated cascade during membrane fusion, helping the lipid bilayers mix. The Rab family of proteins are active when bound to GTP, and inactive when bound to GDP. Hence, they act as guanine nucleotide-dependent molecular switches. Rab-GTP recognizes and binds to long or short-range tethering proteins to capture the target vesicle. These tethers coordinate with SNAREs on the vesicle and the target membrane to assemble the trans SNARE complex that locks the mixing bilayers.
2.6K
01:33Overview of Secretory Vesicles
8.4K
Secretory vesicles, also known as dense core vesicles (DCVs), are membrane-bound vesicles that transport secretory proteins, such as hormones or neurotransmitters. Regulated secretory vesicles transport proteins from the trans-Golgi network to the exterior of the cell. Proteins present in regulated secretory vesicles are required to be rapidly exocytosed in large amounts upon a specific stimulus.
Various proteins regulate the aggregation of molecules inside the secretory vesicles. Chromogranins...
Various proteins regulate the aggregation of molecules inside the secretory vesicles. Chromogranins...
8.4K