Skip to main content
Log in

Endocytic pathways and endosomal trafficking: a primer

  • main topic
  • Published:
Wiener Medizinische Wochenschrift Aims and scope Submit manuscript

Summary

This brief overview of endocytic trafficking is written in honor of Renate Fuchs, who retires this year. In the mid-1980s, Renate pioneered studies on the ion-conducting properties of the recently discovered early and late endosomes and the mechanisms governing endosomal acidification. As described in this review, after uptake through one of many mechanistically distinct endocytic pathways, internalized proteins merge into a common early/sorting endosome. From there they again diverge along distinct sorting pathways, back to the cell surface, on to the trans-Golgi network or across polarized cells. Other transmembrane receptors are packaged into intraluminal vesicles of late endosomes/multivesicular bodies that eventually fuse with and deliver their content to lysosomes for degradation. Endosomal acidification, in part, determines sorting along this pathway. We describe other sorting machinery and mechanisms, as well as the rab proteins and phosphatidylinositol lipids that serve to dynamically define membrane compartments along the endocytic pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Roth TF, Porter KR. Yolk Protein Uptake in the Oocyte of the Mosquito Aedes Aegypti. L. J Cell Biol. 1964;20:313–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Yamada E. The fine structure of the gall bladder epithelium of the mouse. J Biophys Biochem Cytol. 1955;1(5):445–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Moya M, et al. Inhibition of coated pit formation in Hep2 cells blocks the cytotoxicity of diphtheria toxin but not that of ricin toxin. J Cell Biol. 1985;101(2):548–59.

    Article  CAS  PubMed  Google Scholar 

  4. Hansen SH, Sandvig K, van Deurs B. The preendosomal compartment comprises distinct coated and noncoated endocytic vesicle populations. J Cell Biol. 1991;113(4):731–41.

    Article  CAS  PubMed  Google Scholar 

  5. Lamaze C, et al. Interleukin 2 receptors and detergent-resistant membrane domains define a clathrin-independent endocytic pathway. Mol Cell. 2001;7(3):661–71.

    Article  CAS  PubMed  Google Scholar 

  6. Kirkham M, et al. Ultrastructural identification of uncoated caveolin-independent early endocytic vehicles. J Cell Biol. 2005;168(3):465–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Scott CC, Vacca F, Gruenberg J. Endosome maturation, transport and functions. Semin Cell Dev Biol. 2014;31:2–10.

    Article  CAS  PubMed  Google Scholar 

  8. Preston JE, Abbott NJ, Begley DJ. Transcytosis of macromolecules at the blood-brain barrier. Adv Pharmacol. 2014;71:147–63.

    Article  CAS  PubMed  Google Scholar 

  9. Antonescu CN, McGraw TE, Klip A. Reciprocal regulation of endocytosis and metabolism. Cold Spring Harb Perspect Biol. 2014;6(7):a016964.

    Article  PubMed  Google Scholar 

  10. Irannejad R, von Zastrow M. GPCR signaling along the endocytic pathway. Curr Opin Cell Biol. 2014;27:109–16.

    Article  CAS  PubMed  Google Scholar 

  11. Goh LK, Sorkin A. Endocytosis of receptor tyrosine kinases. Cold Spring Harb Perspect Biol. 2013;5(5):a017459.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mellman I, Yarden Y. Endocytosis and cancer. Cold Spring Harb Perspect Biol. 2013;5(12):a016949.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Carpentier JL, et al. Co-localization of 125I-epidermal growth factor and ferritin-low density lipoprotein in coated pits: a quantitative electron microscopic study in normal and mutant human fibroblasts. J Cell Biol. 1982;95(1):73–7.

    Article  CAS  PubMed  Google Scholar 

  14. Neutra MR, et al. Intracellular transport of transferrin- and asialoorosomucoid-colloidal gold conjugates to lysosomes after receptor-mediated endocytosis. J Histochem Cytochem. 1985;33(11):1134–44.

    Article  CAS  PubMed  Google Scholar 

  15. Robinson MS. Forty Years of Clathrin-coated Vesicles. Traffic. 2015;16(12)1210–38.

  16. Kirchhausen T, Owen D, Harrison SC. Molecular structure, function, and dynamics of clathrin-mediated membrane traffic. Cold Spring Harb Perspect Biol. 2014;6(5):a016725.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kirchhausen T. Adaptors for clathrin-mediated traffic. Annu Rev Cell Dev Biol. 1999;15:705–32.

    Article  CAS  PubMed  Google Scholar 

  18. McMahon HT, Boucrot E. Molecular mechanism and physiological functions of clathrin-mediated endocytosis. Nat Rev Mol Cell Biol. 2011;12(8):517–33.

    Article  CAS  PubMed  Google Scholar 

  19. Traub LM, Bonifacino JS. Cargo recognition in clathrin-mediated endocytosis. Cold Spring Harb Perspect Biol. 2013;5(11):a016790.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Cocucci E, et al. The first five seconds in the life of a clathrin-coated pit. Cell. 2012;150(3):495–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Henne WM, et al. FCHo proteins are nucleators of clathrin-mediated endocytosis. Science. 2010;328(5983):1281–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Woodward MP, Roth TF. Coated vesicles: characterization, selective dissociation, and reassembly. Proc Natl Acad Sci U S A. 1978;75(9):4394–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Qualmann B, Koch D, Kessels MM. Let’s go bananas: revisiting the endocytic BAR code. EMBO J. 2011;30(17):3501–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Aguet F, et al. Advances in analysis of low signal-to-noise images link dynamin and AP2 to the functions of an endocytic checkpoint. Dev Cell. 2013;26(3):279–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schmid SL, Frolov VA. Dynamin: functional design of a membrane fission catalyst. Annu Rev Cell Dev Biol. 2011;27:79–105.

    Article  CAS  PubMed  Google Scholar 

  26. Ferguson SM, et al. Coordinated actions of actin and BAR proteins upstream of dynamin at endocytic clathrin-coated pits. Dev Cell. 2009;17(6):811–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rothman JE, Schmid SL. Enzymatic recycling of clathrin from coated vesicles. Cell. 1986;46(1):5–9.

    Article  CAS  PubMed  Google Scholar 

  28. Ungewickell E, et al. Role of auxilin in uncoating clathrin-coated vesicles. Nature. 1995;378(6557):632–5.

    Article  CAS  PubMed  Google Scholar 

  29. Parton RG, Simons K. The multiple faces of caveolae. Nat Rev Mol Cell Biol. 2007;8(3):185–94.

    Article  CAS  PubMed  Google Scholar 

  30. Pelkmans L, Helenius A. Endocytosis via caveolae. Traffic. 2002;3(5):311–20.

    Article  CAS  PubMed  Google Scholar 

  31. Murata M, et al. VIP21/caveolin is a cholesterol-binding protein. Proc Natl Acad Sci U S A. 1995;92(22):10339–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Harder T, Simons K. Caveolae, DIGs, and the dynamics of sphingolipid-cholesterol microdomains. Curr Opin Cell Biol. 1997;9(4):534–42.

    Article  CAS  PubMed  Google Scholar 

  33. Parton RG, del Pozo MA. Caveolae as plasma membrane sensors, protectors and organizers. Nat Rev Mol Cell Biol. 2013;14(2):98–112.

    Article  CAS  PubMed  Google Scholar 

  34. Nassar ZD, Parat MO. Cavin family: new players in the biology of caveolae. Int Rev Cell Mol Biol. 2015;320:235–305.

    Article  PubMed  Google Scholar 

  35. Kiss AL. Caveolae and the regulation of endocytosis. Adv Exp Med Biol. 2012;729:14–28.

    Article  CAS  PubMed  Google Scholar 

  36. Li S, Seitz R, Lisanti MP. Phosphorylation of caveolin by src tyrosine kinases. The alpha-isoform of caveolin is selectively phosphorylated by v-Src in vivo. J Biol Chem. 1996;271(7):3863–8.

    Article  CAS  PubMed  Google Scholar 

  37. Parton RG, Joggerst B, Simons K. Regulated internalization of caveolae. J Cell Biol. 1994;127(5):1199–215.

    Article  CAS  PubMed  Google Scholar 

  38. Henley JR, et al. Dynamin-mediated internalization of caveolae. J Cell Biol. 1998;141(1):85–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sandvig K, van Deurs B. Selective modulation of the endocytic uptake of ricin and fluid phase markers without alteration in transferrin endocytosis. J Biol Chem. 1990;265(11):6382–8.

    CAS  PubMed  Google Scholar 

  40. Doherty GJ, McMahon HT. Mechanisms of endocytosis. Annu Rev Biochem. 2009;78:857–902.

    Article  CAS  PubMed  Google Scholar 

  41. Donaldson JG, Jackson CL. ARF family G proteins and their regulators: roles in membrane transport, development and disease. Nat Rev Mol Cell Biol. 2011;12(6):362–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mayor S, Parton RG, Donaldson JG. Clathrin-independent pathways of endocytosis. In: Schmid ASSL, Zerial M, editor. Endocytosis. 2016. p. pii:a016758. (Cold Spring Harb Perspect Biol).

  43. Boucrot E, et al. Endophilin marks and controls a clathrin-independent endocytic pathway. Nature. 2015;517(7535):460–5.

    Article  CAS  PubMed  Google Scholar 

  44. Huotari J, Helenius A. Endosome maturation. EMBO J. 2011;30(17):3481–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Radhakrishna H, Donaldson JG. ADP-ribosylation factor 6 regulates a novel plasma membrane recycling pathway. J Cell Biol. 1997;139(1):49–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Glebov OO, Bright NA, Nichols BJ. Flotillin-1 defines a clathrin-independent endocytic pathway in mammalian cells. Nat Cell Biol. 2006;8(1):46–54.

    Article  CAS  PubMed  Google Scholar 

  47. Frick M, et al. Coassembly of flotillins induces formation of membrane microdomains, membrane curvature, and vesicle budding. Curr Biol. 2007;17(13):1151–6.

    Article  CAS  PubMed  Google Scholar 

  48. Mayor S, Parton RG, Donaldson JG. Clathrin-independent pathways of endocytosis. Cold Spring Harb Perspect Biol. 2014;6:6.

    Article  Google Scholar 

  49. Maldonado-Baez L, Williamson C, Donaldson JG. Clathrin-independent endocytosis: a cargo-centric view. Exp Cell Res. 2013;319(18):2759–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bitsikas V, Correa IR Jr, Nichols BJ. Clathrin-independent pathways do not contribute significantly to endocytic flux. Elife. 2014;3:e03970.

    PubMed  PubMed Central  Google Scholar 

  51. Elkin SR, et al. A systematic analysis reveals heterogeneous changes in the endocytic activities of cancer cells. Cancer Res. 2015;75(21):4640–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Salzman NH, Maxfield FR. Intracellular fusion of sequentially formed endocytic compartments. J Cell Biol. 1988;106(4):1083–91.

    Article  CAS  PubMed  Google Scholar 

  53. Mellman I, Fuchs R, Helenius A. Acidification of the endocytic and exocytic pathways. Annu Rev Biochem. 1986;55:663–700.

    Article  CAS  PubMed  Google Scholar 

  54. Fuchs R, Schmid SL, Mellman I. A possible role for the Na+, K+-ATPase in regulating ATP-dependent endosome acidification. Proc. Natl. Acad. Sci. (USA). 1989;86(2):539–43

    CAS  PubMed  Google Scholar 

  55. Di Paolo G, De Camilli P. Phosphoinositides in cell regulation and membrane dynamics. Nature. 2006;443(7112):651–7.

    Article  PubMed  Google Scholar 

  56. Bissig C, Gruenberg J. Lipid sorting and multivesicular endosome biogenesis. Cold Spring Harb Perspect Biol. 2013;5(10):a016816.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Lemmon MA. Phosphoinositide recognition domains. Traffic. 2003;4(4):201–13.

    Article  CAS  PubMed  Google Scholar 

  58. Balla T. Inositol-lipid binding motifs: signal integrators through protein-lipid and protein-protein interactions. J Cell Sci. 2005;118(Pt 10):2093–104.

    Article  CAS  PubMed  Google Scholar 

  59. Gillooly DJ, et al. Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells. EMBO J. 2000;19(17):4577–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Klumperman J, Raposo G. The complex ultrastructure of the endolysosomal system. Cold Spring Harb Perspect Biol. 2014;6(10):a016857.

    Article  PubMed  Google Scholar 

  61. Schu PV, et al. Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science. 1993;260(5104):88–91.

    Article  CAS  PubMed  Google Scholar 

  62. Odorizzi G, Babst M, Emr SD. Phosphoinositide signaling and the regulation of membrane trafficking in yeast. Trends Biochem Sci. 2000;25(5):229–35.

    Article  CAS  PubMed  Google Scholar 

  63. Zerial M, McBride H. Rab proteins as membrane organizers. Nat Rev Mol Cell Biol. 2001;2(2):107–17.

    Article  CAS  PubMed  Google Scholar 

  64. Shin HW, et al. An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway. J Cell Biol. 2005;170(4):607–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Novick P, Zerial M. The diversity of Rab proteins in vesicle transport. Curr Opin Cell Biol. 1997;9(4):496–504.

    Article  CAS  PubMed  Google Scholar 

  66. Mellman I. Endocytosis and molecular sorting. Annu Rev Cell Dev Biol. 1996;12:575–625.

    Article  CAS  PubMed  Google Scholar 

  67. Maxfield FR, McGraw TE. Endocytic recycling. Nat Rev Mol Cell Biol. 2004;5(2):121–32.

    Article  CAS  PubMed  Google Scholar 

  68. Hsu VW, Bai M, Li J. Getting active: protein sorting in endocytic recycling. Nat Rev Mol Cell Biol. 2012;13(5):323–8.

    CAS  PubMed  Google Scholar 

  69. van Weering JR, et al. Molecular basis for SNX-BAR-mediated assembly of distinct endosomal sorting tubules. EMBO J. 2012;31(23):4466–80.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Burd C, Cullen PJ. Retromer: a master conductor of endosome sorting. Cold Spring Harb Perspect Biol. 2014;6:2.

    Article  Google Scholar 

  71. Seaman MN, et al. 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. 1997;137(1):79–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Seaman MN, McCaffery JM, Emr SD. A membrane coat complex essential for endosome-to-Golgi retrograde transport in yeast. J Cell Biol. 1998;142(3):665–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Babst M. MVB vesicle formation: ESCRT-dependent, ESCRT-independent and everything in between. Curr Opin Cell Biol. 2011;23(4):452–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hurley JH, Hanson PI. Membrane budding and scission by the ESCRT machinery: it’s all in the neck. Nat Rev Mol Cell Biol. 2010;11(8):556–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Henne WM, Stenmark H, Emr SD. Molecular mechanisms of the membrane sculpting ESCRT pathway. Cold Spring Harb Perspect Biol. 2013;5:9.

    Article  Google Scholar 

  76. Mitsunari T, et al. Clathrin adaptor AP-2 is essential for early embryonal development. Mol Cell Biol. 2005;25(21):9318–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Royle SJ. The cellular functions of clathrin. Cell Mol Life Sci. 2006;63(16):1823–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Song Y, et al. Caveolin-1 knockdown is associated with the metastasis and proliferation of human lung cancer cell line NCI-H460. Biomed Pharmacother. 2012;66(6):439–47.

    Article  CAS  PubMed  Google Scholar 

  79. Zhan P, et al. Expression of caveolin-1 is correlated with disease stage and survival in lung adenocarcinomas. Oncol Rep. 2012;27(4):1072–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Sunaga N, et al. Different roles for caveolin-1 in the development of non-small cell lung cancer versus small cell lung cancer. Cancer Res. 2004;64(12):4277–85.

    Article  CAS  PubMed  Google Scholar 

  81. Le Roy C, Wrana JL. Clathrin- and non-clathrin-mediated endocytic regulation of cell signalling. Nat Rev Mol Cell Biol. 2005;6(2):112–26.

    Article  CAS  PubMed  Google Scholar 

  82. Howes MT, et al. Clathrin-independent carriers form a high capacity endocytic sorting system at the leading edge of migrating cells. J Cell Biol. 2010;190(4):675–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Cossart P, Helenius A. Endocytosis of viruses and bacteria. Cold Spring Harb Perspect Biol. 2014;6:8.

    Article  Google Scholar 

  84. Adjei IM, Sharma B, Labhasetwar V. Nanoparticles: cellular uptake and cytotoxicity. Adv Exp Med Biol. 2014;811:73–91.

    Article  PubMed  Google Scholar 

  85. Stenmark H. Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol. 2009;10(8):513–25.

    Article  CAS  PubMed  Google Scholar 

  86. Seabra MC, Mules EH, Hume AN. Rab GTPases, intracellular traffic and disease. Trends Mol Med. 2002;8(1):23–30.

    Article  CAS  PubMed  Google Scholar 

  87. Cheng KW, et al. Emerging role of RAB GTPases in cancer and human disease. Cancer Res. 2005;65(7):2516–9.

    Article  CAS  PubMed  Google Scholar 

  88. Hutagalung AH, Novick PJ. Role of Rab GTPases in membrane traffic and cell physiology. Physiol Rev. 2011;91(1):119–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Sharma S, Skowronek A, Erdmann KS. The role of the Lowe syndrome protein OCRL in the endocytic pathway. Biol Chem. 2015;396(12):1293–300.

    Article  CAS  PubMed  Google Scholar 

  90. Esposito G, Clara AF, Verstreken P. Synaptic vesicle trafficking and Parkinson’s disease. Dev Neurobiol. 2012;72(1):134–44.

    Article  CAS  PubMed  Google Scholar 

  91. Jiang S, et al. Trafficking regulation of proteins in Alzheimer’s disease. Mol Neurodegener. 2014;9:6.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Goldenring JR. A central role for vesicle trafficking in epithelial neoplasia: intracellular highways to carcinogenesis. Nat Rev Cancer. 2013;13(11):813–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Gauthier NC, Masters TA, Sheetz MP. Mechanical feedback between membrane tension and dynamics. Trends Cell Biol. 2012;22(10):527–35.

    Article  CAS  PubMed  Google Scholar 

  94. Wandinger-Ness A, Zerial M. Rab proteins and the compartmentalization of the endosomal system. Cold Spring Harb Perspect Biol. 2014;6(11):a022616.

    Article  PubMed  Google Scholar 

  95. Pfeffer SR. Rab GTPase regulation of membrane identity. Curr Opin Cell Biol. 2013;25(4):414–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Barr F, Lambright DG. Rab GEFs and GAPs. Curr Opin Cell Biol. 2010;22(4):461–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Gurkan C, et al. Large-scale profiling of Rab GTPase trafficking networks: the membrome. Mol Biol Cell. 2005;16(8):3847–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sandra L. Schmid PhD.

Ethics declarations

Conflicts of interest

S. R. Elkin, A. M. Lakoduk, and S. L. Schmid declare that there are no actual or potential conflicts of interest in relation to this article.

Additional information

Sarah R. Elkin, Ashley M. Lakoduk: These authors contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Elkin, S.R., Lakoduk, A.M. & Schmid, S.L. Endocytic pathways and endosomal trafficking: a primer. Wien Med Wochenschr 166, 196–204 (2016). https://doi.org/10.1007/s10354-016-0432-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10354-016-0432-7

Keywords

Navigation