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

Journal of Cell Science
Matthew N J SeamanSophia Y Breusegem

Abstract

The retromer complex is a vital component of the endosomal protein sorting machinery 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. 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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Citations

Dec 7, 2019·Traffic·Mariana E G de AraujoLukas A Huber
Oct 2, 2019·Proceedings of the National Academy of Sciences of the United States of America·Cecilia Rodriguez-FurlanGlenn R Hicks
Feb 23, 2020·The EMBO Journal·Marlieke Lm JongsmaJacques Neefjes
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May 22, 2021·The Journal of Cell Biology·Rylie B WalshAvital A Rodal
Oct 8, 2020·Nature Communications·Harriet Crawley-SnowdonDavid J Owen

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Datasets Mentioned

BETA
GM130
ABT79

Methods Mentioned

BETA
nucleotide exchange
GTPase
immunoprecipitation
transfections
X-ray
electrophoresis
immunoprecipitations

Software Mentioned

Thermo HSC Studio
Volocity
Origin
Maxquant

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