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Inhibition of TBC1D5 activates Rab7a and can enhance the function of the retromer cargo-selective complex.

Published version
Peer-reviewed

Type

Article

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Authors

Mukadam, Aamir S 
Breusegem, Sophia 

Abstract

The retromer complex is a vital component of the endosomal protein sorting machinery being necessary for sorting into both the endosome-to-Golgi retrieval pathway and also the endosome-to-cell-surface recycling pathway. Retromer mediates cargo selection through a trimeric complex comprising VPS35, VPS29 and VPS26 which is recruited to endosomes by binding to Rab7a and Snx3. Retromer function is linked to two distinct neurodegenerative diseases, Parkinson’s disease and Alzheimer’s disease and modulating retromer function has been proposed as an avenue to explore for a putative therapy in these conditions. We hypothesised that activating Rab7a to promote the recruitment of retromer to endosomes could positively modulate its activity and here we show that inhibition of the GTPase activating protein, TBC1D5, can enhance Rab7a activation and lead to a gain-of-function for retromer.

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Keywords

Journal Title

Journal of cell science

Conference Name

Journal ISSN

0021-9533
1477-9137

Volume Title

131

Publisher

The Company of Biologists Ltd.
Sponsorship
Medical Research Council (MR/L007533/1)