Retromer and Its Role in Regulating Signaling at Endosomes

  • Matthew N. J. SeamanEmail author
Part of the Progress in Molecular and Subcellular Biology book series (PMSB, volume 57)


The retromer complex is a key element of the endosomal protein sorting machinery being involved in trafficking of proteins from endosomes to the Golgi and also endosomes to the cell surface. There is now accumulating evidence that retromer also has a prominent role in regulating the activity of many diverse signaling proteins that traffic through endosomes and this activity has profound implications for the functioning of many different cell and tissue types from neuronal cells to cells of the immune system to specialized polarized epithelial cells of the retina. In this review, the protein composition of the retromer complex will be described along with many of the accessory factors that facilitate retromer-mediated endosomal protein sorting to detail how retromer activity contributes to the regulation of several distinct signaling pathways.



I would like to thank Aamir Mukadam for critical reading of the manuscript. MNJS is funded by the Medical Research Council.


  1. Arighi CN, Hartnell LM, Aguilar RC, Haft CR, Bonifacino JS (2004) Role of the mammalian retromer in sorting of the cation-independent mannose 6-phosphate receptor. J Cell Biol 165(1):123–133CrossRefPubMedPubMedCentralGoogle Scholar
  2. Aubry L, Klein G (2013) True arrestins and arrestin-fold proteins: a structure-based appraisal. Prog Mol Biol Transl Sci. 118:21–56CrossRefPubMedGoogle Scholar
  3. Balana B, Bahima L, Bodhinathan K, Taura JJ, Taylor NM, Nettleton MY, Ciruela F, Slesinger PA (2013) Ras-association domain of sorting Nexin 27 is critical for regulating expression of GIRK potassium channels. PLoS ONE 8(3):e59800CrossRefPubMedPubMedCentralGoogle Scholar
  4. Belenkaya TY, Wu Y, Tang X, Zhou B, Cheng L, Sharma YV, Yan D, Selva EM, Lin X (2008) The retromer complex influences Wnt secretion by recycling wntless from endosomes to the trans-Golgi network. Dev Cell 14(1):120–131CrossRefPubMedGoogle Scholar
  5. Burden JJ, Sun XM, García AB, Soutar AK (2004) Sorting motifs in the intracellular domain of the low density lipoprotein receptor interact with a novel domain of sorting nexin-17. J Biol Chem 279(16):16237–16245CrossRefPubMedGoogle Scholar
  6. Carlton J, Bujny M, Peter BJ, Oorschot VM, Rutherford A, Mellor H, Klumperman J, McMahon HT, Cullen PJ (2004) Sorting nexin-1 mediates tubular endosome-to-TGN transport through coincidence sensing of high- curvature membranes and 3-phosphoinositides. Curr Biol 14(20):1791–800Google Scholar
  7. Chan AS, Clairfeuille T, Landao-Bassonga E, Kinna G, Ng PY, Loo LS, Cheng TS, Zheng M, Hong W, Teasdale RD, Collins BM, Pavlos NJ. (2016) Sorting nexin 27 couples PTHR trafficking to retromer for signal regulation in osteoblasts during bone growth. Mol Biol Cell 27(8):1367–82Google Scholar
  8. Chmiest D, Sharma N, Zanin N, Viaris de Lesegno C, Shafaq-Zadah M, Sibut V, Dingli F, Hupé P, Wilmes S, Piehler J, Loew D, Johannes L, Schreiber G, Lamaze C (2016) Spatiotemporal control of interferon-induced JAK/STAT signaling and gene transcription by the retromer complex. Nat Commun 7:13476CrossRefPubMedPubMedCentralGoogle Scholar
  9. Choy RW, Park M, Temkin P, Herring BE, Marley A, Nicoll RA, von Zastrow M (2014) Retromer mediates a discrete route of local membrane delivery to dendrites. Neuron 82(1):55–62CrossRefPubMedPubMedCentralGoogle Scholar
  10. Collins BM, Norwood SJ, Kerr MC, Mahony D, Seaman MN, Teasdale RD, Owen DJ (2008) Structure of Vps26B and mapping of its interaction with the retromer protein complex. Traffic 9(3):366–379CrossRefPubMedGoogle Scholar
  11. Damseh N, Danson CM, Al-Ashhab M, Abu-Libdeh B, Gallon M, Sharma K, Yaacov B, Coulthard E, Caldwell MA, Edvardson S, Cullen PJ, Elpeleg O (2015) A defect in the retromer accessory protein, SNX27, manifests by infantile myoclonic epilepsy and neurodegeneration. Neurogenetics 16(3):215–221CrossRefPubMedPubMedCentralGoogle Scholar
  12. Derivery E, Sousa C, Gautier JJ, Lombard B, Loew D, Gautreau A (2009) The Arp2/3 activator WASH controls the fission of endosomes through a large multiprotein complex. Dev Cell 17(5):712–723CrossRefPubMedGoogle Scholar
  13. Feinstein TN, Wehbi VL, Ardura JA, Wheeler DS, Ferrandon S, Gardella TJ, Vilardaga JP (2011) Retromer terminates the generation of cAMP by internalized PTH receptors. Nat Chem Biol 7(5):278–284CrossRefPubMedPubMedCentralGoogle Scholar
  14. Franch-Marro X, Wendler F, Guidato S, Griffith J, Baena-Lopez A, Itasaki N, Maurice MM, Vincent JP (2008) Wingless secretion requires endosome-to-Golgi retrieval of Wntless/Evi/Sprinter by the retromer complex. Nat Cell Biol 10(2):170–177CrossRefPubMedGoogle Scholar
  15. Freeman CL, Hesketh G, Seaman MN (2014) RME-8 coordinates the activity of the WASH complex with the function of the retromer SNX dimer to control endosomal tubulation. J Cell Sci 127(Pt 9):2053–2070CrossRefPubMedPubMedCentralGoogle Scholar
  16. Gallon M, Clairfeuille T, Steinberg F, Mas C, Ghai R, Sessions RB, Teasdale RD, Collins BM, Cullen PJ (2014) A unique PDZ domain and arrestin-like fold interaction reveals mechanistic details of endocytic recycling by SNX27-retromer. Proc Natl Acad Sci U S A 111(35):E3604–E3613CrossRefPubMedPubMedCentralGoogle Scholar
  17. Ghai R, Mobli M, Norwood SJ, Bugarcic A, Teasdale RD, King GF, Collins BM (2011) Phox homology band 4.1/ezrin/radixin/moesin-like proteins function as molecular scaffolds that interact with cargo receptors and Ras GTPases. Proc Natl Acad Sci U S A 108(19):7763–7768CrossRefPubMedPubMedCentralGoogle Scholar
  18. Gurevich VV, Gurevich EV (2014) Overview of different mechanisms of arrestin-mediated signaling. Curr Protoc Pharmacol 1:67Google Scholar
  19. Haft CR, de la Luz Sierra M, Bafford R, Lesniak MA, Barr VA, Taylor SI (2000) Human orthologs of yeast vacuolar protein sorting proteins Vps 26, 29, and 35: assembly into multimeric complexes. Mol Biol Cell 11(12):4105–4116CrossRefPubMedPubMedCentralGoogle Scholar
  20. Harbour ME, Breusegem SY, Seaman MN (2012) Recruitment of the endosomal WASH complex is mediated by the extended ‘tail’ of Fam21 binding to the retromer protein Vps35. Biochem J 442(1):209–220CrossRefPubMedGoogle Scholar
  21. Harbour ME, Seaman MN (2011) Evolutionary variations of VPS29, and their implications for the heteropentameric model of retromer. Commun Integr Biol 4(5):619–622CrossRefPubMedPubMedCentralGoogle Scholar
  22. Harterink M, Port F, Lorenowicz MJ, McGough IJ, Silhankova M, Betist MC, van Weering JR, van Heesbeen RG, Middelkoop TC, Basler K, Cullen PJ, Korswagen HC (2011) A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion. Nat Cell Biol 13(8):914–923CrossRefPubMedPubMedCentralGoogle Scholar
  23. Helfer E, Harbour ME, Henriot V, Lakisic G, Sousa-Blin C, Volceanov L, Seaman MN, Gautreau A (2013) Endosomal recruitment of the WASH complex: active sequences and mutations impairing interaction with the retromer. Biol Cell 105(5):191–207CrossRefPubMedGoogle Scholar
  24. Herrero A, Matallanas D, Kolch W (2016) The spatiotemporal regulation of RAS signaling. Biochem Soc Trans 44(5):1517–1522CrossRefGoogle Scholar
  25. Horazdovsky BF, Davies B, Seaman MNJ, McLauglin SA, Yoon S-K, Emr SD (1997) A Yeast homolog of Snx1, Vps5p forms a membrane associated complex with Vps17p and is required for recycling of the vacuolar sorting receptor, Vps10p. Mol Biol Cell 8:1529–1541Google Scholar
  26. Hussain NK, Diering GH, Sole J, Anggono V, Huganir RL (2014) Sorting Nexin 27 regulates basal and activity-dependent trafficking of AMPARs. Proc Natl Acad Sci U S A 111(32):11840–11845CrossRefPubMedPubMedCentralGoogle Scholar
  27. Jia D, Gomez TS, Billadeau DD, Rosen MK (2012) Multiple repeat elements within the FAM21 tail link the WASH actin regulatory complex to the retromer. Mol Biol Cell 23(12):2352–2361CrossRefPubMedPubMedCentralGoogle Scholar
  28. Lee S, Chang J, Blackstone C (2016) FAM21 directs SNX27-retromer cargoes to the plasma membrane by preventing transport to the Golgi apparatus. Nat Commun 9(7):10939CrossRefGoogle Scholar
  29. Loo LS, Tang N, Al-Haddawi M, Dawe GS, Hong W (2014) A role for sorting nexin 27 in AMPA receptor trafficking. Nat Commun 5:3176CrossRefPubMedPubMedCentralGoogle Scholar
  30. Lunn ML, Nassirpour R, Arrabit C, Tan J, McLeod I, Arias CM, Sawchenko PE, Yates JR 3rd, Slesinger PA (2007) A unique sorting nexin regulates trafficking of potassium channels via a PDZ domain interaction. Nat Neurosci 10(10):1249–1259CrossRefPubMedGoogle Scholar
  31. McGarvey JC, Xiao K, Bowman SL, Mamonova T, Zhang Q, Bisello A, Sneddon WB, Ardura JA, Jean-Alphonse F, Vilardaga JP, Puthenveedu MA, Friedman PA (2016) Actin-Sorting Nexin 27 (SNX27)-retromer complex mediates rapid parathyroid hormone receptor recycling. J Biol Chem 291(21):10986–101002CrossRefPubMedPubMedCentralGoogle Scholar
  32. McGough IJ, Steinberg F, Jia D, Barbuti PA, McMillan KJ, Heesom KJ, Whone AL, Caldwell MA, Billadeau DD, Rosen MK, Cullen PJ (2014) Retromer binding to FAM21 and the WASH complex is perturbed by the Parkinson disease-linked VPS35(D620 N) mutation. Curr Biol 24(14):1670–1676CrossRefPubMedPubMedCentralGoogle Scholar
  33. Munsie LN, Milnerwood AJ, Seibler P, Beccano-Kelly DA, Tatarnikov I, Khinda J, Volta M, Kadgien C, Cao LP, Tapia L, Klein C, Farrer MJ (2015) Retromer-dependent neurotransmitter receptor trafficking to synapses is altered by the Parkinson’s disease VPS35 mutation p. D620N. Hum Mol Genet 24(6):1691–1703CrossRefPubMedGoogle Scholar
  34. Pan CL, Baum PD, Gu M, Jorgensen EM, Clark SG, Garriga G (2008) C. elegans AP-2 and retromer control Wnt signaling by regulating mig-14/Wntless. Dev Cell 14(1):132–139CrossRefPubMedGoogle Scholar
  35. Port F, Kuster M, Herr P, Furger E, Bänziger C, Hausmann G, Basler K (2008) Wingless secretion promotes and requires retromer-dependent cycling of Wntless. Nat Cell Biol 10(2):178–185CrossRefPubMedGoogle Scholar
  36. Schuh AL, Audhya A (2014) The ESCRT machinery: from the plasma membrane to endosomes and back again. Crit Rev Biochem Mol Biol. 49(3):242–261Google Scholar
  37. Seaman MN (2004) Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J Cell Biol 165(1):111–122CrossRefPubMedPubMedCentralGoogle Scholar
  38. Seaman MN (2012) The retromer complex—endosomal protein recycling and beyond. J Cell Sci 125(Pt 20):4693–4702CrossRefPubMedPubMedCentralGoogle Scholar
  39. Seaman MN, Gautreau A, Billadeau DD (2013) Retromer-mediated endosomal protein sorting: all WASHed up! Trends Cell Biol 23(11):522–528CrossRefPubMedPubMedCentralGoogle Scholar
  40. Seaman MN, Marcusson EG, Cereghino JL, Emr SD (1997) Endosome to Golgi retrieval of the vacuolar protein sorting receptor, Vps10p, requires the function of the VPS29, VPS30, and VPS35 gene products. J Cell Biol 137(1):79–92CrossRefPubMedPubMedCentralGoogle Scholar
  41. Seaman MN, McCaffery JM, Emr SD (1998) A membrane coat complex essential for endosome-to-Golgi retrograde transport in yeast. J Cell Biol 142(3):665–681CrossRefPubMedPubMedCentralGoogle Scholar
  42. Shi H, Rojas R, Bonifacino JS, Hurley JH (2006) The retromer subunit Vps26 has an arrestin fold and binds Vps35 through its C-terminal domain. Nat Struct Mol Biol 13(6):540–548CrossRefPubMedPubMedCentralGoogle Scholar
  43. Steinberg F, Gallon M, Winfield M, Thomas EC, Bell AJ, Heesom KJ, Tavaré JM, Cullen PJ (2013) A global analysis of SNX27-retromer assembly and cargo specificity reveals a function in glucose and metal ion transport. Nat Cell Biol 15(5):461–471CrossRefPubMedPubMedCentralGoogle Scholar
  44. Strochlic TI, Setty TG, Sitaram A, Burd CG (2007) Grd19/Snx3p functions as a cargo-specific adapter for retromer-dependent endocytic recycling. J Cell Biol 177(1):115–125CrossRefPubMedPubMedCentralGoogle Scholar
  45. Swarbrick JD, Shaw DJ, Chhabra S, Ghai R, Valkov E, Norwood SJ, Seaman MN, Collins BM (2011) VPS29 is not an active metallo-phosphatase but is a rigid scaffold required for retromer interaction with accessory proteins. PLoS ONE 6(5):e20420CrossRefPubMedPubMedCentralGoogle Scholar
  46. Temkin P, Lauffer B, Jäger S, Cimermancic P, Krogan NJ, von Zastrow M (2011) SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signaling receptors. Nat Cell Biol 13(6):715–721CrossRefPubMedPubMedCentralGoogle Scholar
  47. Tian Y, Tang FL, Sun X, Wen L, Mei L, Tang BS, Xiong WC (2015) VPS35-deficiency results in an impaired AMPA receptor trafficking and decreased dendritic spine maturation. Mol Brain 8(1):70CrossRefPubMedPubMedCentralGoogle Scholar
  48. van Weering JR, Cullen PJ (2014) Membrane-associated cargo recycling by tubule-based endosomal sorting. Semin Cell Dev Biol 31:40–47CrossRefPubMedGoogle Scholar
  49. Wang S, Tan KL, Agosto MA, Xiong B, Yamamoto S, Sandoval H, Jaiswal M, Bayat V, Zhang K, Charng WL, David G, Duraine L, Venkatachalam K, Wensel TG, Bellen HJ (2014) The retromer complex is required for rhodopsin recycling and its loss leads to photoreceptor degeneration. PLoS Biol 12(4):e1001847CrossRefPubMedPubMedCentralGoogle Scholar
  50. Wang X, Zhao Y, Zhang X, Badie H, Zhou Y, Mu Y, Loo LS, Cai L, Thompson RC, Yang B, Chen Y, Johnson PF, Wu C, Bu G, Mobley WC, Zhang D, Gage FH, Ranscht B, Zhang YW, Lipton SA, Hong W, Xu H (2013) Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down’s syndrome. Nat Med 19(4):473–480CrossRefPubMedPubMedCentralGoogle Scholar
  51. Xia WF, Tang FL, Xiong L, Xiong S, Jung JU, Lee DH, Li XS, Feng X, Mei L, Xiong WC (2013) Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling. J Cell Biol 200(6):821–837CrossRefPubMedPubMedCentralGoogle Scholar
  52. Yang PT, Lorenowicz MJ, Silhankova M, Coudreuse DY, Betist MC, Korswagen HC (2008) Wnt signaling requires retromer-dependent recycling of MIG-14/Wntless in Wnt-producing cells. Dev Cell 14(1):140–147CrossRefPubMedGoogle Scholar
  53. Zavodszky E, Seaman MN, Moreau K, Jimenez-Sanchez M, Breusegem SY, Harbour ME, Rubinsztein DC (2014) Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy. Nat Commun 5:3828CrossRefPubMedPubMedCentralGoogle Scholar
  54. Zhang P, Wu Y, Belenkaya TY, Lin X (2011) SNX3 controls Wingless/Wnt secretion through regulating retromer-dependent recycling of Wntless. Cell Res 21(12):1677–1690CrossRefPubMedPubMedCentralGoogle Scholar
  55. Zhou M, Wiener H, Su W, Zhou Y, Liot C, Ahearn I, Hancock JF, Philips MR (2016) VPS35 binds farnesylated N-Ras in the cytosol to regulate N-Ras trafficking. J Cell Biol 214(4):445–458CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Cambridge Institute for Medical Research, University of CambridgeCambridgeUK

Personalised recommendations