SNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion

Ian J McGough, Reinoud E A de Groot, Adam P Jellett, Marco C Betist, Katherine C Varandas, Chris M Danson, Kate J Heesom, Hendrik C Korswagen, Peter J Cullen

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Wntless transports Wnt morphogens to the cell surface and is required for Wnt secretion and morphogenic gradients formation. Recycling of endocytosed Wntless requires the sorting nexin-3 (SNX3)-retromer-dependent endosome-to-Golgi transport pathway. Here we demonstrate the essential role of SNX3-retromer assembly for Wntless transport and report that SNX3 associates with an evolutionary conserved endosome-associated membrane re-modelling complex composed of MON2, DOPEY2 and the putative aminophospholipid translocase, ATP9A. In vivo suppression of Ce-mon-2, Ce-pad-1 or Ce-tat-5 (respective MON2, DOPEY2 and ATP9A orthologues) phenocopy a loss of SNX3-retromer function, leading to enhanced lysosomal degradation of Wntless and a Wnt phenotype. Perturbed Wnt signalling is also observed upon overexpression of an ATPase-inhibited TAT-5(E246Q) mutant, suggesting a role for phospholipid flippase activity during SNX3-retromer-mediated Wntless sorting. Together, these findings provide in vitro and in vivo mechanistic details to describe SNX3-retromer-mediated transport during Wnt secretion and the formation of Wnt-morphogenic gradients.

Original languageEnglish
Pages (from-to)3737
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 13 Sep 2018

Keywords

  • Animals
  • Biological Transport
  • Caenorhabditis elegans
  • Endosomes/metabolism
  • Golgi Apparatus/metabolism
  • Green Fluorescent Proteins/metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mutation
  • Phenotype
  • Phospholipid Transfer Proteins/metabolism
  • Protein Binding
  • Protein Domains
  • Proteomics
  • Proton-Translocating ATPases/metabolism
  • RNA Interference
  • Sorting Nexins/metabolism
  • Transgenes
  • Vesicular Transport Proteins/metabolism
  • Wnt Proteins/metabolism

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