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Journal Article•DOI•

A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion

Martin Harterink1, Fillip Port2, Magdalena J. Lorenowicz1, Ian J. McGough3, Marie Silhankova1, Marco C. Betist1, Jan R.T. van Weering3, Roy G. H. P. van Heesbeen1, Teije C. Middelkoop1, Konrad Basler2, Peter J. Cullen3, Hendrik C. Korswagen1 •
American Academy of Arts and Sciences1, University of Zurich2, University of Bristol3
01 Aug 2011-Nature Cell Biology (Nature Publishing Group)-Vol. 13, Iss: 8, pp 914-923
TL;DR: It is found that the unrelated sorting nexin, SNX3, has an evolutionarily conserved function in Wls recycling and Wnt secretion and it is demonstrated that SNX 3 interacts directly with the cargo-selective subcomplex of the retromer to sort Wls into a morphologically distinct retrieval pathway.
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.

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Citations
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Journal Article•DOI•
Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

[...]

Tamas Balla1•
National Institutes of Health1
01 Jul 2013-Physiological Reviews
TL;DR: This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.
Abstract: Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.

1,239 citations

Cites background from "A SNX3-dependent retromer pathway m..."

  • ...These enzymes facilitate budding of vesicles 1031Physiol Rev • VOL 93 • JULY 2013 • www.prv.org by 10.220.33.3 on O ctober 27, 2017 http://physrev.physiology.org/ D ow nloaded from from the TGN and associate with the TGN-localized RabA4b protein (a Rab11 homolog of the plant) at the region corresponding to the Rab11 interaction site in PI4KIII ....

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  • ...It has been shown that PtdIns4P in the Golgi/TGN is critical to the membrane recruitment of various clathrin adaptors, such as the heterotetrameric AP-1 (1680) and monomeric GGAs (1509, 1671) and that PI4K2A, rather than the type III PI4KB, was the important enzyme in this process (1671, 1680)....

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  • ...Therefore, it was surprising to find the majority of PI4K2A and PI4K2B enzymes in intracellular membranes, mostly associated with the TGN and endosomes by immunocytochemical analysis (83, 1060, 1680)....

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  • ...For example, SNX4 controls trafficking of TfRs between the early and recycling endosomes (1571), and SNX3 is central to a newly recognized unique retromer pathway by which the Wnt sorting receptor Wntless is retrieved from the endosomes to the TGN (307, 576)....

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Journal Article•DOI•
Active Wnt proteins are secreted on exosomes

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Julia Christina Gross1, Varun Chaudhary1, Kerstin Bartscherer1, Michael Boutros1•
German Cancer Research Center1
01 Oct 2012-Nature Cell Biology
TL;DR: It is demonstrated that exosomes carry Wnts on their surface to induce Wnt signalling activity in target cells and an evolutionarily conserved functional role of extracellular vesicular transport of Wnt proteins is demonstrated.
Abstract: Wnt signalling has important roles during development and in many diseases As morphogens, hydrophobic Wnt proteins exert their function over a distance to induce patterning and cell differentiation decisions Recent studies have identified several factors that are required for the secretion of Wnt proteins; however, how Wnts travel in the extracellular space remains a largely unresolved question Here we show that Wnts are secreted on exosomes both during Drosophila development and in human cells We demonstrate that exosomes carry Wnts on their surface to induce Wnt signalling activity in target cells Together with the cargo receptor Evi/WIs, Wnts are transported through endosomal compartments onto exosomes, a process that requires the R-SNARE Ykt6 Our study demonstrates an evolutionarily conserved functional role of extracellular vesicular transport of Wnt proteins

817 citations

Journal Article•DOI•
The retromer complex - endosomal protein recycling and beyond.

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Matthew N.J. Seaman1•
University of Cambridge1
15 Oct 2012-Journal of Cell Science
TL;DR: The interactions between the retromer complex and other macromolecular protein complexes now show how endosomal protein sorting is coordinated with actin assembly and movement along microtubules, and placeretromer squarely at the centre of a complex set of protein machinery that governs endosome-to-Golgi protein sorting.
Abstract: The retromer complex is a vital element of the endosomal protein sorting machinery that is conserved across all eukaryotes. Retromer is most closely associated with the endosome-to-Golgi retrieval pathway and is necessary to maintain an active pool of hydrolase receptors in the trans-Golgi network. Recent progress in studies of retromer have identified new retromer-interacting proteins, including the WASH complex and cargo such as the Wntless/MIG-14 protein, which now extends the role of retromer beyond the endosome-to-Golgi pathway and has revealed that retromer is required for aspects of endosome-to-plasma membrane sorting and regulation of signalling events. The interactions between the retromer complex and other macromolecular protein complexes now show how endosomal protein sorting is coordinated with actin assembly and movement along microtubules, and place retromer squarely at the centre of a complex set of protein machinery that governs endosomal protein sorting. Dysregulation of retromer-mediated endosomal protein sorting leads to various pathologies, including neurodegenerative diseases such as Alzheimer disease and spastic paraplegia and the mechanisms underlying these pathologies are starting to be understood. In this Commentary, I will highlight recent advances in the understanding of retromer-mediated endosomal protein sorting and discuss how retromer contributes to a diverse set of physiological processes.

431 citations

Cites background from "A SNX3-dependent retromer pathway m..."

  • ...…element of retromer (i.e. Snx1) is not required for Wntless/MIG-14 retrieval and led to suggestions that two functionally distinct retromer complexes operate in endosomal protein sorting in C. elegans, a Snx3-containing retromer, and a Snx-BAR-containing retromer complex (Harterink et al., 2011)....

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  • ...elegans have revealed a role for Snx3 in retromer-mediated Wntless/MIG-14 retrieval (Harterink et al., 2011; Zhang et al., 2011)....

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  • ...Studies in C. elegans have revealed a role for Snx3 in retromer-mediated Wntless/MIG-14 retrieval (Harterink et al., 2011; Zhang et al., 2011)....

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  • ...For example, the P2Y1 receptor requires the Snx-BAR dimer, but not the cargo-selective trimer, for its localisation, whereas the opposite might be true for the Wntless/MIG-14 protein in C. elegans (Nisar et al., 2010; Harterink et al., 2011)....

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  • ...elegans, a Snx3-containing retromer, and a Snx-BAR-containing retromer complex (Harterink et al., 2011)....

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Journal Article•DOI•
Endosome maturation, transport and functions.

[...]

Cameron C. Scott1, Fabrizio Vacca1, Jean Gruenberg1•
University of Geneva1
01 Jul 2014-Seminars in Cell & Developmental Biology
TL;DR: The current understanding of the organization and functions of the endocytic pathway, differences across species, and the process of endosome maturation are summarized.

390 citations

Journal Article•DOI•
Retromer: A Master Conductor of Endosome Sorting

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Christopher G. Burd1, Peter J. Cullen2•
Yale University1, University of Bristol2
01 Feb 2014-Cold Spring Harbor Perspectives in Biology
TL;DR: The increasing body of evidence that implicates an ancient evolutionary conserved complex, termed "retromer," as a master conductor in the complex orchestration of multiple cargo-sorting events within the endosomal network is discussed.
Abstract: The endosomal network comprises an interconnected network of membranous compartments whose primary function is to receive, dissociate, and sort cargo that originates from the plasma membrane and the biosynthetic pathway. A major challenge in cell biology is to achieve a thorough molecular description of how this network operates, and in so doing, how defects contribute to the etiology and pathology of human disease. We discuss the increasing body of evidence that implicates an ancient evolutionary conserved complex, termed "retromer," as a master conductor in the complex orchestration of multiple cargo-sorting events within the endosomal network.

371 citations

Cites background from "A SNX3-dependent retromer pathway m..."

  • ...Indeed, in C. elegans, the retromer-mediated sorting of CED-1 is SNX-BAR-retromer dependent but is independent of the SNX3 retromer (Chen et al. 2010; Harterink et al. 2011; Lu et al. 2011)....

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  • ...Furthermore, the morphological profile of each transport carrier is distinct: SNX-BAR retromer residing on nonbranched tubules 170–230 nm in length and 20–50 nm in diameter (Mari et al. 2008), whereas SNX3 retromer is associated with small clathrin-coated vesicular profiles (Harterink et al. 2011)....

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  • ...The specific binding of SNX3 to PtdIns(3)P targets the CSC to early endosomes (Harterink et al. 2011; Vardarajan et al. 2012), whereas the ability of VPS35 to bind Rab7GTP associates the CSC with late endosomes (Nakada-Tsukui et al. 2005; Rojas et al. 2008; Seaman et al. 2009; Balderhaar et al.…...

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  • ...…the missorting of internalized Wntless into the lysosomal degradative pathway (this is also observed in mammalian cell culture upon RNAi-mediated suppression), a reduction in the steady-state level of Wntless, and a defect in Wnt secretion and hence Wnt gradient formation (Harterink et al. 2011)....

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  • ...Here the functional retromer is composed of the direct binding of the CSC to the early endosome associated non-BAR domain-containing SNX3, an association that is independent of the SNXBAR retromer subunits (Harterink et al. 2011; Zhang et al. 2011)....

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References
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Journal Article•DOI•
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Susanne Bolte, Fabrice P. Cordelières1•
Curie Institute1
01 Dec 2006-Journal of Microscopy
TL;DR: A novel toolbox for subcellular colocalization analysis under ImageJ is created that integrates current global statistic methods and a novel object‐based approach to assess proteins residing on intracellular structures by fluorescence microscopy.
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  • ...Pearson’s coefficients were calculated using the ICA plug-in for ImageJ (NIH) or by using Velocity co-localization software (Perkin Elmer) as describe...

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Journal Article•DOI•
Systematic functional analysis of the Caenorhabditis elegans genome using RNAi

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Ravi S. Kamath1, Andrew G. Fraser1, Andrew G. Fraser2, Yan Dong1, Gino B. Poulin1, Richard Durbin2, Monica Gotta1, Alexander Kanapin3, Nathalie Le Bot1, Sergio Moreno1, Sergio Moreno4, Marc Sohrmann2, David P. Welchman1, Peder Zipperlen1, Julie Ahringer1 •
University of Cambridge1, Wellcome Trust Sanger Institute2, European Bioinformatics Institute3, Spanish National Research Council4
16 Jan 2003-Nature
TL;DR: It is found that genes of similar functions are clustered in distinct, multi-megabase regions of individual chromosomes; genes in these regions tend to share transcriptional profiles.
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Book Chapter•DOI•
Chapter 19 DNA Transformation

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Craig C. Mello1, Andrew Fire2•
University of Massachusetts Amherst1, Carnegie Institution for Science2
01 Jan 1995-Methods in Cell Biology
TL;DR: This chapter discusses DNA transformation, which provides experimental links between molecular structure and phenotype in a whole organism and three forms of heritable DNA transformation have been observed in C. elegans.
Abstract: Publisher Summary This chapter discusses DNA transformation. DNA transformation assays in a whole organism provide experimental links between molecular structure and phenotype. Experiments with transgenic Caenorhabditis elegans start in general with the injection of DNA into the adult gonad. Effects on phenotype or gene expression patterns can be analyzed either in F1 progeny derived from the injected animals or in derived transgenic lines. Germ-line transformation has been achieved by microinjection of DNA directly into oocyte nuclei or by microinjection of DNA into the cytoplasm of the hermaphrodite syncytial gonad. Three forms of heritable DNA transformation have been observed in C. elegans are: (1) extra chromosomal transformation; (2) non-homologous integration; and (3) homologous integration. Setting up microinjection in a laboratory already equipped for C. elegans genetics and molecular biology requires a modest investment in space and money. A separate easily scoreable marker gene to identify transformed animals can be extremely useful in a variety of injection experiments. The propensity for injected DNA molecules to recombine with each other generally allows one to coinject the selectable marker with a DNA segment to be tested for activity.

1,032 citations

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Henry F. Epstein, C Shakes Diane
01 Jan 1995
TL;DR: Genetic and culture methods neurobiology cell biology and molecular biology genomics and informatics appendices - additional information and resources, Caenorhabditis genetics centre (laboratory designations), gene names and descriptions.
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Journal Article•DOI•
Direct and Long-Range Action of a Wingless Morphogen Gradient

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Myriam Zecca1, Konrad Basler1, Gary Struhl2•
University of Zurich1, Columbia University2
29 Nov 1996-Cell
TL;DR: Findings indicate that wild-type Wg acts at long range, up-regulating the transcription of particular target genes as a function of concentration and distance from secreting cells, and is interpreted as evidence that Wg can act directly and at longrange as a gradient morphogen during normal development.

749 citations

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