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

Author

Listed:
  • Ian J. McGough

    (University of Bristol
    The Francis Crick Institute)

  • Reinoud E. A. Groot

    (Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht)

  • Adam P. Jellett

    (University of Bristol)

  • Marco C. Betist

    (Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht)

  • Katherine C. Varandas

    (University of California, San Francisco
    The Rockefeller University)

  • Chris M. Danson

    (University of Bristol)

  • Kate J. Heesom

    (University of Bristol)

  • Hendrik C. Korswagen

    (Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht)

  • Peter J. Cullen

    (University of Bristol)

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.

Suggested Citation

  • Ian J. McGough & Reinoud E. A. Groot & Adam P. Jellett & Marco C. Betist & Katherine C. Varandas & Chris M. Danson & Kate J. Heesom & Hendrik C. Korswagen & Peter J. Cullen, 2018. "SNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06114-3
    DOI: 10.1038/s41467-018-06114-3
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    Cited by:

    1. Rebeka Butkovič & Alexander P. Walker & Michael D. Healy & Kerrie E. McNally & Meihan Liu & Tineke Veenendaal & Kohji Kato & Nalan Liv & Judith Klumperman & Brett M. Collins & Peter J. Cullen, 2024. "Mechanism and regulation of cargo entry into the Commander endosomal recycling pathway," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Lin Bai & Bhawik K. Jain & Qinglong You & H. Diessel Duan & Mehmet Takar & Todd R. Graham & Huilin Li, 2021. "Structural basis of the P4B ATPase lipid flippase activity," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

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