Identification of molecular heterogeneity in SNX27-retromer-mediated endosome-to-plasma-membrane recycling

Ian J Mcgough, Florian Steinberg, Matthew J Gallon, Ayaka Yatsu, Norihiko Ohbayashi, Kate J Heesom, Mitsunori Fukuda, Peter J Cullen

Research output: Contribution to journalArticle (Academic Journal)

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Abstract

Retromer is a protein assembly that orchestrates the sorting of transmembrane cargo proteins into endosome-to-Golgi and endosome-to-plasma-membrane transport pathways. Here, we have employed quantitative proteomics to define the interactome of human VPS35, the core retromer component. This has identified a number of new interacting proteins, including ankyrin-repeat domain 50 (ANKRD50), seriologically defined colon cancer antigen 3 (SDCCAG3) and VPS9-ankyrin-repeat protein (VARP, also known as ANKRD27). Depletion of these proteins resulted in trafficking defects of retromer-dependent cargo, but differential and cargo-specific effects suggested a surprising degree of functional heterogeneity in retromer-mediated endosome-to-plasma-membrane sorting. Extending this, suppression of the retromer-associated WASH complex did not uniformly affect retromer cargo, thereby confirming cargo-specific functions for retromer-interacting proteins. Further analysis of the retromer–VARP interaction identified a role for retromer in endosome-to-melanosome transport. Suppression of VPS35 led to mistrafficking of the melanogenic enzymes, tyrosinase and tryrosine-related protein 1 (Tyrp1), establishing that retromer acts in concert with VARP in this trafficking pathway. Overall, these data reveal hidden complexities in retromer-mediated sorting and open up new directions in our molecular understanding of this essential sorting complex.
Original languageEnglish
Pages (from-to)4940-4953
Number of pages14
JournalJournal of Cell Science
Volume127
Issue number22
Early online date14 Nov 2014
DOIs
Publication statusE-pub ahead of print - 14 Nov 2014

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