γ-secretase facilitates retromer-mediated retrograde transport

Area of Science:

• Cell Biology
• Neuroscience
• Molecular Biology

Background:

• The retromer complex is essential for retrograde protein transport from endosomes to the trans-Golgi network (TGN).
• γ-secretase is a protease complex implicated in neurodegenerative diseases like Alzheimer's disease (AD).
• Previous studies suggest an interaction between retromer and γ-secretase, but its functional significance remains unclear.

Purpose of the Study:

• To investigate the functional consequences of the interaction between the retromer complex and γ-secretase.
• To determine if γ-secretase activity influences retromer-mediated retrograde trafficking.

Main Methods:

• Utilized cultured human epithelial cells.
• Inhibited γ-secretase activity using a specific inhibitor (XXI).
• Genetically eliminated γ-secretase by knocking out its catalytic subunit (PS1).
• Assessed the trafficking of various retromer-dependent and independent cargos.

Main Results:

• Inhibition or genetic elimination of γ-secretase impaired endosome-to-TGN trafficking of retromer-dependent cargos (DMT1-II, CIMPR, shiga toxin).
• Trafficking of retromer-independent cargos was unaffected by γ-secretase inhibition.
• γ-secretase inhibition and PS1 knockout reduced the interaction between γ-secretase and retromer but not cargo-retromer or cargo-γ-secretase interactions.
• These treatments did not alter Rab7-GTP levels, indicating retromer-cargo binding was not directly affected.

Conclusions:

• The interaction between γ-secretase and retromer facilitates retromer-mediated retrograde trafficking.
• γ-secretase activity is necessary for efficient endosome-to-TGN transport of specific cargos.
• This finding provides new insights into the molecular mechanisms underlying neurodegenerative diseases linked to retromer and γ-secretase dysfunction.