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

McGough, Ian J., de Groot, Reinoud E. A., Jellett, Adam P., Betist, Marco C., Varandas, Katherine C., Danson, Chris M., Heesom, Kate J., Korswagen, Hendrik C., Cullen, Peter J.·2018·Nature Communications
DOI 10.1038/s41467-018-06114-3PMC PMC6137200
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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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  • SNX3 directly binds to a subset of cargo containing the sequence motif [+/-]-x-∅-x-[L/M], with many of these cargoes trafficked through the retrograde endosome-to-TGN pathway.

    “SNX3 directly binds to a subset of cargo containing the poorly defined sequence motif [+/-]-x-∅-x-[L/M] (∅ -bulky aromatic residue) with many of these cargoes trafficked through the retrograde endosome-to-TGN pathway [25,30,66,67].”

    From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [67]

    The Introduction (page unavailable) says SNX3-retromer associates with Wntless through two Φ-X-[L/M] motifs and retrieves Wntless from early endosomes to the Golgi. It identifies VPS35, rather than cargo, as the protein SNX3 directly binds. The cited passages do not establish the fuller [+/-]-x-∅-x-[L/M] motif or that many cargoes bearing it take this route. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Endosomal retrieval and recycling is orchestrated through a specialised endosomal nanodomain, the retrieval sub-domain.

    “and is orchestrated through a specialised endosomal nanodomain, the retrieval sub-domain”

    From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [15]

    The Discussion (page unavailable) proposes a diffusion-restricted sub-domain in which membrane bending is coordinated with SNX3-retromer capture of Wntless cargo. It does not identify that domain as a specialised endosomal nanodomain called the “retrieval sub-domain,” or establish this as a general mechanism for endosomal retrieval and recycling. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The SNX3-Retromer assembly is essential for the sequence-dependent retrieval and recycling of cargoes.

    “An additional cargo adaptor complex essential for the sequence-dependent retrieval and recycling of cargoes is the sorting nexin-3 (SNX3)-Retromer assembly [25,30,66,67].”

    From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [67]

  • Endosomal cargo retrieval and recycling are orchestrated by several multi-protein assemblies including SNX27-Retromer and SNX3-Retromer, SNX17-Retriever and associated Commander super-assembly, the WASH complex and its regulatory MUST complex, and the SNX-BAR proteins and ESCPE-1.

    “Orchestrating endosomal cargo retrieval and recycling are several multi-protein assemblies that include sorting nexin-27 (SNX27)-Retromer and SNX3-Retromer8–16, SNX17-Retriever and associated Commander super-assembly17–22, the branched F-actin polymerising WASH complex and its regulatory MAGE-L2/USP7/TRIM27 (MUST) complex23–25, and the SNX-BAR proteins and endosomal sorting complex required for ex”

    From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [15]

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Metadata

Authors
McGough, I. J., de Groot, R. E. A., Jellett, A. P., Betist, M. C., Varandas, K. C., Danson, C. M., Heesom, K. J., Korswagen, H. C., & Cullen, P. J.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-09-13
Volume
9
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-018-06114-3
PMC
PMC6137200
Cited by
87
References
3
Language
en
Licence
Funders
  • Wellcome Trust (089928, 085743, 104568, 083474)
  • Biotechnology and Biological Sciences Research Council (BB/I011412/1)
  • KWF Kankerbestrijding (HUBR 2008-4114)

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