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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Biological Transport, Active
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / growth & development
  • Caenorhabditis elegans / metabolism
  • Drosophila / genetics
  • Drosophila / growth & development
  • Drosophila / metabolism
  • Endosomes / metabolism
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Models, Biological
  • RNA Interference
  • Signal Transduction
  • Sorting Nexins / antagonists & inhibitors
  • Sorting Nexins / genetics
  • Sorting Nexins / metabolism*
  • Wnt Proteins / metabolism*
  • trans-Golgi Network / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • SNX3 protein, human
  • Sorting Nexins
  • Wnt Proteins