title: A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion.
abstract: Wnt proteins are lipid-modified glycoproteins that play a central role in development, adult tissue homeostasis and disease. Secretion of Wnt proteins is mediated by the Wnt-binding protein Wntless (Wls), which transports Wnt from the Golgi network to the cell surface for release. It has recently been shown that recycling of Wls through a retromer-dependent endosome-to-Golgi trafficking pathway is required for efficient Wnt secretion, but the mechanism of this retrograde transport pathway is poorly understood. Here, we report that Wls recycling is mediated through a retromer pathway that is independent of the retromer sorting nexins SNX1-SNX2 and SNX5-SNX6. We have found that the unrelated sorting nexin, SNX3, has an evolutionarily conserved function in Wls recycling and Wnt secretion and show that SNX3 interacts directly with the cargo-selective subcomplex of the retromer to sort Wls into a morphologically distinct retrieval pathway. These results demonstrate that SNX3 is part of an alternative retromer pathway that functionally separates the retrograde transport of Wls from other retromer cargo.
authors: Hubrecht Institute, Royal Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
authors: Martin
authors: M
authors: Harterink
authors: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors: Fillip
authors: F
authors: Port
authors: Hubrecht Institute, Royal Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
authors: Magdalena J
authors: MJ
authors: Lorenowicz
authors: Henry Wellcome Integrated Signaling Laboratories, Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors: Ian J
authors: IJ
authors: McGough
authors: Hubrecht Institute, Royal Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
authors: Marie
authors: M
authors: Silhankova
authors: Hubrecht Institute, Royal Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
authors: Marco C
authors: MC
authors: Betist
authors: Henry Wellcome Integrated Signaling Laboratories, Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors: Jan R T
authors: JRT
authors: van Weering
authors: Hubrecht Institute, Royal Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
authors: Roy G H P
authors: RGHP
authors: van Heesbeen
authors: Hubrecht Institute, Royal Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
authors: Teije C
authors: TC
authors: Middelkoop
authors: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors: Konrad
authors: K
authors: Basler
authors: Henry Wellcome Integrated Signaling Laboratories, Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors: Peter J
authors: PJ
authors: Cullen
authors: Hubrecht Institute, Royal Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
authors: Hendrik C
authors: HC
authors: Korswagen
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001693:Biological Transport, Active; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008954:Models, Biological; D034622:RNA Interference; D015398:Signal Transduction; D058305:Sorting Nexins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C513980:SNX3 protein, human; D058305:Sorting Nexins; D051153:Wnt Proteins