A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion

M Harterink, F Port, M.J Lorenowicz, I.J McGough, M Silhankova, M.C Betist, J.R.T van Weering, R.G.H.P van Heesbeen, T.C Middlekoop, K Basler, P.J Cullen, H.C Korswagen

Research output: Contribution to journalArticle (Academic Journal)

190 Citations (Scopus)

Abstract

Wnt proteins are lipid-modified glycoproteins that play a central role in development, adult tissue homeostasis and disease. Secretion of Wnt proteins is mediated by the Wnt-binding protein Wntless (Wls), which transports Wnt from the Golgi network to the cell surface for release. It has recently been shown that recycling of Wls through a retromer-dependent endosome-to-Golgi trafficking pathway is required for efficient Wnt secretion, but the mechanism of this retrograde transport pathway is poorly understood. Here, we report that Wls recycling is mediated through a retromer pathway that is independent of the retromer sorting nexins SNX1-SNX2 and SNX5-SNX6. We have found that the unrelated sorting nexin, SNX3, has an evolutionarily conserved function in Wls recycling and Wnt secretion and show that SNX3 interacts directly with the cargo-selective subcomplex of the retromer to sort Wls into a morphologically distinct retrieval pathway. These results demonstrate that SNX3 is part of an alternative retromer pathway that functionally separates the retrograde transport of Wls from other retromer cargo.
Original languageEnglish
Pages (from-to)914 - 923
Number of pages10
JournalNature Cell Biology
Volume13
Issue number8
DOIs
Publication statusPublished - Jul 2011

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    Harterink, M., Port, F., Lorenowicz, M. J., McGough, I. J., Silhankova, M., Betist, M. C., van Weering, J. R. T., van Heesbeen, R. G. H. P., Middlekoop, T. C., Basler, K., Cullen, P. J., & Korswagen, H. C. (2011). A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion. Nature Cell Biology, 13 (8), 914 - 923. https://doi.org/10.1038/ncb2281