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

  • Nat Cell Biol. 2011 Jul 3;13(8):914-923. doi: 10.1038/ncb2281.
Martin Harterink  1 ,  Fillip Port  #  2 ,  Magdalena J Lorenowicz  #  1 ,  Ian J McGough  #  3 ,  Marie Silhankova  1 ,  Marco C Betist  1 ,  Jan R T van Weering  3 ,  Roy G H P van Heesbeen  1 ,  Teije C Middelkoop  1 ,  Konrad Basler  2 ,  Peter J Cullen  3 ,  Hendrik C Korswagen  1
Affiliations
  • 1. Hubrecht Institute, Royal Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
  • 2. Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
  • 3. Henry Wellcome Integrated Signaling Laboratories, Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom.
  • # Contributed equally.
PMID: 21725319 DOI: 10.1038/ncb2281
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.