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

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

    Research output: Contribution to journalArticle

    53 Citations (Scopus)

    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 cargospecific effects suggested a surprising degree of functional heterogeneity in retromer-mediated endosome-to-plasma-membrane sorting. Extending this, suppression of the retromer-associatedWASH 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
    DOIs
    Publication statusPublished - 2014

    Keywords

    • Retromer
    • SNX27
    • Sorting nexin
    • VARP
    • VPS35

    ASJC Scopus subject areas

    • Cell Biology

    Fingerprint Dive into the research topics of 'Identification of molecular heterogeneity in SNX27-retromermediated endosome-to-plasma-membrane recycling'. Together they form a unique fingerprint.

  • Cite this

    McGough, I. J., Steinberg, F., Gallon, M., Yatsu, A., Ohbayashi, N., Heesom, K. J., Fukuda, M., & Cullen, P. J. (2014). Identification of molecular heterogeneity in SNX27-retromermediated endosome-to-plasma-membrane recycling. Journal of cell science, 127(22), 4940-4953. https://doi.org/10.1242/jcs.156299