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

McGough, Ian J., Steinberg, Florian, Gallon, Matthew, Yatsu, Ayaka, Ohbayashi, Norihiko, Heesom, Kate J., Fukuda, Mitsunori, Cullen, Peter J.·2014·Journal of Cell Science
DOI 10.1242/jcs.156299PMC PMC4231307
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Abstract

Retromer is a protein assembly that orchestrates 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). 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 miss trafficking 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.

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  • The Retromer sub-domain proximity proteome included the RAB7 GAP TBC1D5, the RAB21/RAB32/RAB38 GEF VARP, and the RAB10 GEFs DENND4A and DENND4C.

    “These included known Retromer accessory proteins, the RAB7 GAP TBC1D546,77–81, the RAB21/RAB32/RAB38 GEF VARP (a.k.a. ANKRD27)47,48,82, and the RAB10 GEFs DENND4A and DENND4C83,84.”

    From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [48]

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Research works printed but not linked: 46

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Metadata

Authors
McGough, I. J., Steinberg, F., Gallon, M., Yatsu, A., Ohbayashi, N., Heesom, K. J., Fukuda, M., & Cullen, P. J.
Venue
Journal of Cell Science
Publisher
The Company of Biologists
Published
2014-01-01
ISSN
  • 1477-9137
  • 0021-9533
DOI
10.1242/jcs.156299
PMC
PMC4231307
Cited by
87
References
3
Language
en
Licence
creativecommons.org/licenses/by/3.0 (am, 2694 d)

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