2. Academic Validation
  3. SNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion

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

  • Nat Commun. 2018 Sep 13;9(1):3737. doi: 10.1038/s41467-018-06114-3.
Ian J McGough 1 2,  Reinoud E A de Groot 3,  Adam P Jellett 1,  Marco C Betist 3,  Katherine C Varandas 4 5,  Chris M Danson 1,  Kate J Heesom 6,  Hendrik C Korswagen 7,  Peter J Cullen 8
Affiliations

Affiliations

  • 1 School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK.
  • 2 The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
  • 3 Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, Utrecht, 3584 CT, The Netherlands.
  • 4 Program in Cell Biology, University of California, San Francisco, 16th Street, San Francisco, CA, 94158, USA.
  • 5 Laboratory of Developmental Genetics, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.
  • 6 Proteomics Facility, School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK.
  • 7 Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, Utrecht, 3584 CT, The Netherlands. [email protected].
  • 8 School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK. [email protected].
PMID: 30213940 DOI: 10.1038/s41467-018-06114-3
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.

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