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Rme-8 depletion perturbs Notch recycling and predisposes to pathogenic signaling.


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Authors

Gomez-Lamarca, Maria J 
Snowdon, Laura A 
Seib, Ekatarina 
Klein, Thomas 
Bray, Sarah J 

Abstract

Notch signaling is a major regulator of cell fate, proliferation, and differentiation. Like other signaling pathways, its activity is strongly influenced by intracellular trafficking. Besides contributing to signal activation and down-regulation, differential fluxes between trafficking routes can cause aberrant Notch pathway activation. Investigating the function of the retromer-associated DNAJ protein Rme-8 in vivo, we demonstrate a critical role in regulating Notch receptor recycling. In the absence of Rme-8, Notch accumulated in enlarged tubulated Rab4-positive endosomes, and as a consequence, signaling was compromised. Strikingly, when the retromer component Vps26 was depleted at the same time, Notch no longer accumulated and instead was ectopically activated. Likewise, depletion of ESCRT-0 components Hrs or Stam in combination with Rme-8 also led to high levels of ectopic Notch activity. Together, these results highlight the importance of Rme-8 in coordinating normal endocytic recycling route and reveal that its absence predisposes toward conditions in which pathological Notch signaling can occur.

Description

Keywords

Animals, Disintegrins, Drosophila Proteins, Drosophila melanogaster, Endosomal Sorting Complexes Required for Transport, Gene Knockdown Techniques, Metalloendopeptidases, Protein Transport, Receptors, Notch, Signal Transduction, Vesicular Transport Proteins, Wnt1 Protein

Journal Title

J Cell Biol

Conference Name

Journal ISSN

0021-9525
1540-8140

Volume Title

201

Publisher

Rockefeller University Press
Sponsorship
Medical Research Council (G0800034)
Medical Research Council (MR/L007177/1)
This work was funded by an MRC programme grant [G0800034] to SJB. LAS was the recipient of a BBSRC PhD studentship. ES and TK were funded by the DFG [Sachbeihilfe KL 1028/5-­1].