biostudies-literatureMcGough IJNIDA NIH HHSKWF Kankerbestrijding (Dutch Cancer Society)Medical Research CouncilDutch Research Council (NWO)Wellcome TrustBiotechnology and Biological Sciences Research Council3737https://www.ebi.ac.uk/biostudies/studies/S-EPMC6137200biostudies-literatureUnknown9(1)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 oveNature communicationsSNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion.PMC6137200083474104568/Z/14/ZHUBR 2008-41141514461089928104568F31 DA036290BB/I011412/1822.02.012085743Heesom KJDanson CMde Groot REAVarandas KCBetist MCMcGough IJJellett APKorswagen HCCullen PJfalseSNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion.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 ove2018-01-01T00:00:00Z2018 Sep2025-04-04T23:35:23.721Z2019-03-26T23:56:14ZS-EPMC61372003021394010.1038/s41467-018-06114-3