Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of pathogen entry through the endosomal compartments

Key Points

  • The endocytic pathway is composed of two sorting stations, the early and late endosomes, and the lysosomes. Internalized molecules first enter in early endosomes from where they can be recycled to the plasma membrane or transported to late endosomes. Once in late endosomes, molecules can be sorted to the trans-Golgi network, selectively transported to the plasma membrane or packaged into lysosomes, where degradation occurs.

  • Large particles, such as bacteria, are taken up by phagocytosis and are eventually degraded in phagolysosomes — this process helps to clear the extracellular environment of pathogens. Because the nascent phagosomes are unable to kill microorganisms, phagosomal maturation occurs through sequential interactions with early and late endosomes and finally with lysosomes.

  • Pathogens and their products have evolved ways to use and benefit from the endocytic entry routes into the cell. To avoid degradation in lysosomes, pathogens must escape from endosomes before these fuse with lysosomes or they must prevent phagosomal maturation.

  • Some pathogenic agents have acquired the capacity to hijack intrinsic endosomal properties to avoid the lysosomes. For example, the anthrax toxin and vesicular stomatitis virus seem to (mis-)use mechanisms that regulate the dynamics of multivesicular endosomes.

  • Other pathogens, and in particular bacteria, have adopted strategies, which can be very diverse, to change the properties of endosomes and lysosomes. Common themes include the modification of the phosphoinositide content to change the apparent identity of organelles. This can result in the prevention of phagosomal maturation at early or later stages, the modification of lipid-raft properties by bacterial products and alterations of phagosomal and endosomal localization and motility.

  • Trypanosoma cruzi, a parasitic protozoa, uses yet another strategy to enter the cell. As opposed to most other pathogens, T. cruzi does not avoid lysosomes, but requires them for efficient infection. Fusion of the parasite with the lysosomes is required for the release of the parasite into the cytoplasm, where replication occurs.

Abstract

Several pathogens — bacteria, viruses and parasites — must enter mammalian cells for survival, replication and immune-system evasion. These pathogens generally make use of existing cellular pathways that are designed for nutrient uptake, receptor downregulation and signalling. Because most of these pathways end in lysosomes, an organelle that is capable of killing microorganisms, pathogens have developed remarkable means to avoidinteractions with this lytic organelle.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic view of the endocytic pathway.
Figure 2: Multivesicular endosomes and viral nucleocapsids.
Figure 3: Pathogens and toxins in the endocytic pathway.

Similar content being viewed by others

References

  1. Conner, S. D. & Schmid, S. L. Regulated portals of entry into the cell. Nature 422, 37–44 (2003).

    CAS  PubMed  Google Scholar 

  2. Marsh, M. & Helenius, A. Virus entry: open sesame. Cell 124, 729–740 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Mayor, S. & Riezman, H. Sorting GPI-anchored proteins. Nature Rev. Mol. Cell Biol. 5, 110–120 (2004).

    CAS  Google Scholar 

  4. Pelkmans, L. & Zerial, M. Kinase-regulated quantal assemblies and kiss-and-run recycling of caveolae. Nature 436, 128–133 (2005).

    CAS  PubMed  Google Scholar 

  5. Kirkham, M. et al. Ultrastructural identification of uncoated caveolin-independent early endocytic vehicles. J. Cell Biol. 168, 465–476 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Rink, J., Ghigo, E., Kalaidzidis, Y. & Zerial, M. Rab conversion as a mechanism of progression from early to late endosomes. Cell 122, 735–749 (2005).

    CAS  PubMed  Google Scholar 

  7. Vonderheit, A. & Helenius, A. Rab7 associates with early endosomes to mediate sorting and transport of Semliki forest virus to late endosomes. PLoS Biol. 3, e233 (2005).

    PubMed  PubMed Central  Google Scholar 

  8. Gruenberg, J. The endocytic pathway: a mosaic of domains. Nature Rev. Mol. Cell Biol. 2, 721–730 (2001).

    CAS  Google Scholar 

  9. Zerial, M. & McBride, H. Rab proteins as membrane organizers. Nature Rev. Mol. Cell Biol. 2, 107–117 (2001).

    CAS  Google Scholar 

  10. Gruenberg, J. Lipids in endocytic membrane transport and sorting. Curr. Opin. Cell Biol. 15, 382–388 (2003).

    CAS  PubMed  Google Scholar 

  11. Gillooly, D. J. et al. Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells. EMBO J. 19, 4577–4588 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Simonsen, A., Wurmser, A. E., Emr, S. D. & Stenmark, H. The role of phosphoinositides in membrane transport. Curr. Opin. Cell Biol. 13, 485–492 (2001).

    CAS  PubMed  Google Scholar 

  13. Petiot, A., Faure, J., Stenmark, H. & Gruenberg, J. PI3P signaling regulates receptor sorting but not transport in the endosomal pathway. J. Cell Biol. 162, 971–979 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Balla, T. Inositol–lipid binding motifs: signal integrators through protein–lipid and protein–protein interactions. J. Cell Sci. 118, 2093–2104 (2005).

    CAS  PubMed  Google Scholar 

  15. Hoepfner, S. et al. Modulation of receptor recycling and degradation by the endosomal kinesin KIF16B. Cell 121, 437–450 (2005).

    CAS  PubMed  Google Scholar 

  16. Shin, H. W. et al. An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway. J. Cell Biol. 170, 607–618 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Michell, R. H., Heath, V. L., Lemmon, M. A. & Dove, S. K. Phosphatidylinositol 3,5-bisphosphate: metabolism and cellular functions. Trends Biochem. Sci. 31, 52–63 (2006).

    CAS  PubMed  Google Scholar 

  18. Efe, J. A., Botelho, R. J. & Emr, S. D. The Fab1 phosphatidylinositol kinase pathway in the regulation of vacuole morphology. Curr. Opin. Cell Biol. 17, 402–408 (2005).

    CAS  PubMed  Google Scholar 

  19. Eugster, A. et al. Ent5p is required with Ent3p and Vps27p for ubiquitin-dependent protein sorting into the multivesicular body. Mol. Biol. Cell 15, 3031–3041 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Friant, S. et al. Ent3p Is a PtdIns(3,5)P2 effector required for protein sorting to the multivesicular body. Dev. Cell 5, 499–511 (2003).

    CAS  PubMed  Google Scholar 

  21. Whitley, P. et al. Identification of mammalian Vps24p as an effector of phosphatidylinositol 3,5-bisphosphate-dependent endosome compartmentalization. J. Biol. Chem. 278, 38786–38795 (2003).

    CAS  PubMed  Google Scholar 

  22. Kobayashi, T. et al. A lipid associated with the antiphospholipid syndrome regulates endosome structure/function. Nature 392, 193–197 (1998).

    CAS  PubMed  Google Scholar 

  23. Mayran, M., Parton, R. G. & Gruenberg, J. Annexin II regulates multivesicular endosome biogenesis in the degradation pathway of animal cells. EMBO J. 13, 3242–3253 (2003).

    Google Scholar 

  24. Katzmann, D. J., Odorizzi, G. & Emr, S. D. Receptor downregulation and multivesicular-body sorting. Nature Rev. Mol. Cell Biol. 3, 893–905 (2002).

    CAS  Google Scholar 

  25. Gruenberg, J. & Stenmark, H. The biogenesis of multivesicular endosomes. Nature Rev. Mol. Cell Biol. 5, 317–323 (2004).

    CAS  Google Scholar 

  26. Hemler, M. E. Tetraspanin functions and associated microdomains. Nature Rev. Mol. Cell Biol. 6, 801–811 (2005).

    CAS  Google Scholar 

  27. Murk, J. L., Stoorvogel, W., Kleijmeer, M. J. & Geuze, H. J. The plasticity of multivesicular bodies and the regulation of antigen presentation. Semin. Cell Dev. Biol. 13, 303–311 (2002).

    CAS  PubMed  Google Scholar 

  28. Kobayashi, T. et al. Separation and characterization of late endosomal membrane domains. J. Biol. Chem. 277, 32157–32164 (2002).

    CAS  PubMed  Google Scholar 

  29. Mobius, W. et al. Recycling compartments and the internal vesicles of multivesicular bodies harbor most of the cholesterol found in the endocytic pathway. Traffic 4, 222–231 (2003).

    CAS  PubMed  Google Scholar 

  30. Murk, J. L. et al. Endosomal compartmentalization in three dimensions: implications for membrane fusion. Proc. Natl Acad. Sci. USA 100, 13332–13337 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Miaczynska, M., Pelkmans, L. & Zerial, M. Not just a sink: endosomes in control of signal transduction. Curr. Opin. Cell Biol. 16, 400–406 (2004).

    CAS  PubMed  Google Scholar 

  32. Dikic, I. Mechanisms controlling EGF receptor endocytosis and degradation. Biochem. Soc. Trans. 31, 1178–1181 (2003).

    CAS  PubMed  Google Scholar 

  33. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).

    CAS  PubMed  Google Scholar 

  34. Martinon, F. & Tschopp, J. NLRs join TLRs as innate sensors of pathogens. Trends Immunol. 26, 447–454 (2005).

    CAS  PubMed  Google Scholar 

  35. Trombetta, E. S. & Mellman, I. Cell biology of antigen processing in vitro and in vivo. Annu. Rev. Immunol. 23, 975–1028 (2005).

    CAS  PubMed  Google Scholar 

  36. Thery, C., Zitvogel, L. & Amigorena, S. Exosomes: composition, biogenesis and function. Nature Rev. Immunol. 2, 569–579 (2002).

    CAS  Google Scholar 

  37. Jutras, I. & Desjardins, M. Phagocytosis: at the crossroads of innate and adaptive immunity. Annu. Rev. Cell Dev. Biol. 21, 511–527 (2005).

    CAS  PubMed  Google Scholar 

  38. Botelho, R. J., Scott, C. C. & Grinstein, S. Phosphoinositide involvement in phagocytosis and phagosome maturation. Curr. Top. Microbiol. Immunol. 282, 1–30 (2004).

    CAS  PubMed  Google Scholar 

  39. Abrami, L., Reig, N. & van der Goot, F. G. Anthrax toxin: the long and winding road that leads to the kill. Trends Microbiol. 13, 72–78 (2005).

    CAS  PubMed  Google Scholar 

  40. Krantz, B. A., Finkelstein, A. & Collier, R. J. Protein translocation through the anthrax toxin transmembrane pore is driven by a proton gradient. J. Mol. Biol. 355, 968–979 (2006).

    CAS  PubMed  Google Scholar 

  41. Wolfe, J. T., Krantz, B. A., Rainey, G. J., Young, J. A. & Collier, R. J. Whole-cell voltage clamp measurements of anthrax toxin pore current. J. Biol. Chem. 280, 39417–39422 (2005).

    CAS  PubMed  Google Scholar 

  42. Rainey, G. J. et al. Receptor-specific requirements for anthrax toxin delivery into cells. Proc. Natl Acad. Sci. USA 102, 13278–13283 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Abrami, L., Lindsay, M., Parton, R. G., Leppla, S. H. & van der Goot, F. G. Membrane insertion of anthrax protective antigen and cytoplasmic delivery of lethal factor occur at different stages of the endocytic pathway. J. Cell Biol. 166, 645–651 (2004). Describes the journey of the anthrax toxin through the endocytic pathway and, in particular, the release of the enzymatic subunits into the lumen of intralumenal vesicles and subsequently into the cytoplasm by the back fusion of these vesicles with the limiting membrane.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Lichty, B. D., Power, A. T., Stojdl, D. F. & Bell, J. C. Vesicular stomatitis virus: re-inventing the bullet. Trends Mol. Med. 10, 210–216 (2004).

    CAS  PubMed  Google Scholar 

  45. Le Blanc, I. et al. Endosome-to-cytosol transport of viral nucleocapsids. Nature Cell Biol. 7, 653–664 (2005). Challenges the textbook view that viral fusion and the release of the nucleocapsid into the cytoplasm are concomitant events. It shows that the virus fuses with intralumenal vesicles, and therefore, leads to the release of the nucleocapsid into the lumen of these vesicles. Release into the cytoplasm occurs at a later stage.

    CAS  PubMed  Google Scholar 

  46. Vidricaire, G., Imbeault, M. & Tremblay, M. J. Endocytic host cell machinery plays a dominant role in intracellular trafficking of incoming human immunodeficiency virus type 1 in human placental trophoblasts. J. Virol. 78, 11904–11915 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Vidricaire, G. & Tremblay, M. J. Rab5 and Rab7, but not ARF6, govern the early events of HIV-1 infection in polarized human placental cells. J. Immunol. 175, 6517–6530 (2005).

    CAS  PubMed  Google Scholar 

  48. Pizarro-Cerda, J. & Cossart, P. Bacterial adhesion and entry into host cells. Cell 124, 715–727 (2006).

    CAS  PubMed  Google Scholar 

  49. Tweten, R. K. Cholesterol-dependent cytolysins, a family of versatile pore-forming toxins. Infect. Immun. 73, 6199–6209 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Henry, R. et al. Cytolysin-dependent delay of vacuole maturation in macrophages infected with Listeria monocytogenes. Cell Microbiol. 8, 107–119 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Shaughnessy, L. M., Hoppe, A. D., Christensen, K. A. & Swanson, J. A. Membrane perforations inhibit lysosome fusion by altering pH and calcium in Listeria monocytogenes vacuoles. Cell Microbiol. 8, 781–792 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Cheng, L. W. et al. Use of RNA interference in Drosophila S2 cells to identify host pathways controlling compartmentalization of an intracellular pathogen. Proc. Natl Acad. Sci. USA 102, 13646–13651 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Beauregard, K. E., Lee, K. D., Collier, R. J. & Swanson, J. A. pH-dependent perforation of macrophage phagosomes by listeriolysin O from Listeria monocytogenes. J. Exp. Med. 186, 1159–1163 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Myers, J. T., Tsang, A. W. & Swanson, J. A. Localized reactive oxygen and nitrogen intermediates inhibit escape of Listeria monocytogenes from vacuoles in activated macrophages. J. Immunol. 171, 5447–5453 (2003).

    CAS  PubMed  Google Scholar 

  55. Arellano-Reynoso, B. et al. Cyclic β-1,2-glucan is a Brucella virulence factor required for intracellular survival. Nature Immunol. 6, 618–625 (2005). Describes the role of cyclic β 1,2-glucan in extracting host cholesterol from membranes and thereby disrupting rafts. The consequence of this disruption is the fusion of Brucella -containing vacuoles with lysosomes.

    CAS  Google Scholar 

  56. Simons, K. & Ikonen, E. Functiomal rafts in cell membranes. Nature 387, 569–572 (1997).

    CAS  PubMed  Google Scholar 

  57. Dermine, J. F. et al. Flotillin-1-enriched lipid raft domains accumulate on maturing phagosomes. J. Biol. Chem. 276, 18507–18512 (2001).

    CAS  PubMed  Google Scholar 

  58. Dermine, J. F., Goyette, G., Houde, M., Turco, S. J. & Desjardins, M. Leishmania donovani lipophosphoglycan disrupts phagosome microdomains in J774 macrophages. Cell. Microbiol. 7, 1263–1270 (2005).

    CAS  PubMed  Google Scholar 

  59. Spath, G. F., Garraway, L. A., Turco, S. J. & Beverley, S. M. The role(s) of lipophosphoglycan (LPG) in the establishment of Leishmania major infections in mammalian hosts. Proc. Natl Acad. Sci. USA 100, 9536–9541 (2003).

    PubMed  PubMed Central  Google Scholar 

  60. Behnia, R. & Munro, S. Organelle identity and the signposts for membrane traffic. Nature 438, 597–604 (2005).

    CAS  PubMed  Google Scholar 

  61. Vergne, I., Chua, J., Singh, S. B. & Deretic, V. Cell biology of Mycobacterium tuberculosis phagosome. Annu. Rev. Cell Dev. Biol. 20, 367–394 (2004).

    CAS  PubMed  Google Scholar 

  62. Fratti, R. A., Backer, J. M., Gruenberg, J., Corvera, S. & Deretic, V. Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest. J. Cell Biol. 154, 631–644 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Vieira, O. V. et al. Acquisition of Hrs, an essential component of phagosomal maturation, is impaired by mycobacteria. Mol. Cell. Biol. 24, 4593–4604 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Kusner, D. J. Mechanisms of mycobacterial persistence in tuberculosis. Clin. Immunol. 114, 239–247 (2005).

    CAS  PubMed  Google Scholar 

  65. Vergne, I., Chua, J. & Deretic, V. Tuberculosis toxin blocking phagosome maturation inhibits a novel Ca2+/calmodulin–PI3K hVPS34 cascade. J. Exp. Med. 198, 653–659 (2003).

    PubMed  PubMed Central  Google Scholar 

  66. Malik, Z. A., Iyer, S. S. & Kusner, D. J. Mycobacterium tuberculosis phagosomes exhibit altered calmodulin-dependent signal transduction: contribution to inhibition of phagosome–lysosome fusion and intracellular survival in human macrophages. J. Immunol. 166, 3392–3401 (2001).

    CAS  PubMed  Google Scholar 

  67. Vergne, I. et al. Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 102, 4033–4038 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Karlsson, K. & Carlsson, S. R. Sorting of lysosomal membrane glycoproteins lamp-1 and lamp-2 into vesicles distinct from mannose 6-phosphate receptor/γ-adaptin vesicles at the trans-Golgi network. J. Biol. Chem. 273, 18966–18973 (1998).

    CAS  PubMed  Google Scholar 

  69. Patel, J. C., Rossanese, O. W. & Galan, J. E. The functional interface between Salmonella and its host cell: opportunities for therapeutic intervention. Trends Pharmacol. Sci. 26, 564–570 (2005).

    CAS  PubMed  Google Scholar 

  70. Marcus, S. L., Wenk, M. R., Steele-Mortimer, O. & Finlay, B. B. A synaptojanin-homologous region of Salmonella typhimurium SigD is essential for inositol phosphatase activity and Akt activation. FEBS Lett. 494, 201–207 (2001).

    CAS  PubMed  Google Scholar 

  71. Hernandez, L. D., Hueffer, K., Wenk, M. R. & Galan, J. E. Salmonella modulates vesicular traffic by altering phosphoinositide metabolism. Science 304, 1805–1807 (2004). Describes the role of Salmonella effectors in modulating the phosphoinositide content of the vacuole and therefore interfering with phagosomal maturation.

    CAS  PubMed  Google Scholar 

  72. Dukes, J. D. et al. The secreted Salmonella dublin phosphoinositide phosphatase, SopB, localises to PtdIns(3)P containing endosomes and perturbs normal endosome to lysosome trafficking. Biochem. J. 395, 239–247 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Gouin, E., Welch, M. D. & Cossart, P. Actin-based motility of intracellular pathogens. Curr. Opin. Microbiol. 8, 35–45 (2005).

    CAS  PubMed  Google Scholar 

  74. Henry, T., Gorvel, J. P. & Meresse, S. Molecular motors hijacking by intracellular pathogens. Cell Microbiol. 8, 23–32 (2006).

    CAS  PubMed  Google Scholar 

  75. Salcedo, S. P. & Holden, D. W. SseG, a virulence protein that targets Salmonella to the Golgi network. EMBO J. 22, 5003–5014 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Jordens, I. et al. The Rab7 effector protein RILP controls lysosomal transport by inducing the recruitment of dynein–dynactin motors. Curr. Biol. 11, 1680–1685 (2001).

    CAS  PubMed  Google Scholar 

  77. Cantalupo, G., Alifano, P., Roberti, V., Bruni, C. B. & Bucci, C. Rab-interacting lysosomal protein (RILP): the Rab7 effector required for transport to lysosomes. EMBO J. 20, 683–693 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Harrison, R. E., Bucci, C., Vieira, O. V., Schroer, T. A. & Grinstein, S. Phagosomes fuse with late endosomes and/or lysosomes by extension of membrane protrusions along microtubules: role of Rab7 and RILP. Mol. Cell. Biol. 23, 6494–6506 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Guignot, J. et al. Microtubule motors control membrane dynamics of Salmonella-containing vacuoles. J. Cell Sci. 117, 1033–1045 (2004).

    CAS  PubMed  Google Scholar 

  80. Harrison, R. E. et al. Salmonella impairs RILP recruitment to Rab7 during maturation of invasion vacuoles. Mol. Biol. Cell 15, 3146–3154 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Boucrot, E., Henry, T., Borg, J. P., Gorvel, J. P. & Meresse, S. The intracellular fate of Salmonella depends on the recruitment of kinesin. Science 308, 1174–1178 (2005). Describes the identification of the SifA effector as a novel mammalian protein that downregulates the recruitment of kinesin to endosomes and therefore regulates endosomal membrane dynamics.

    CAS  PubMed  Google Scholar 

  82. Kuhle, V., Jackel, D. & Hensel, M. Effector proteins encoded by Salmonella pathogenicity island 2 interfere with the microtubule cytoskeleton after translocation into host cells. Traffic 5, 356–370 (2004).

    CAS  PubMed  Google Scholar 

  83. Knodler, L. A. & Steele-Mortimer, O. The Salmonella effector PipB2 affects late endosome/lysosome distribution to mediate Sif extension. Mol. Biol. Cell 16, 4108–4123 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Andrade, L. O. & Andrews, N. W. The Trypanosoma cruzi-host-cell interplay: location, invasion, retention. Nature Rev. Microbiol. 3, 819–823 (2005).

    CAS  Google Scholar 

  85. Tardieux, I. et al. Lysosome recruitment and fusion are early events required for trypanosome invasion of mammalian cells. Cell 71, 1117–1130 (1992).

    CAS  PubMed  Google Scholar 

  86. Woolsey, A. M. et al. Novel PI 3-kinase-dependent mechanisms of trypanosome invasion and vacuole maturation. J. Cell Sci. 116, 3611–3622 (2003).

    CAS  PubMed  Google Scholar 

  87. Coppens, I. et al. Toxoplasma gondii sequesters lysosomes from mammalian hosts in the vacuolar space. Cell 125, 261–274 (2006).

    CAS  PubMed  Google Scholar 

  88. Soldati, D., Foth, B. J. & Cowman, A. F. Molecular and functional aspects of parasite invasion. Trends Parasitol. 20, 567–574 (2004).

    CAS  PubMed  Google Scholar 

  89. Coppens, I., Sinai, A. P. & Joiner, K. A. Toxoplasma gondii exploits host low-density lipoprotein receptor-mediated endocytosis for cholesterol acquisition. J. Cell Biol. 149, 167–180 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Pelchen-Matthews, A., Raposo, G. & Marsh, M. Endosomes, exosomes and Trojan viruses. Trends Microbiol. 12, 310–316 (2004).

    CAS  PubMed  Google Scholar 

  91. Hurley, J. H. & Emr, S. D. The ESCRT complexes: structure and mechanism of a membrane-trafficking network. Annu. Rev. Biophys. Biomol. Struct. 35, 277–298 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Pornillos, O. et al. HIV Gag mimics the Tsg101-recruiting activity of the human Hrs protein. J. Cell Biol. 162, 425–434 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Booth, A. M. et al. Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. J. Cell Biol. 172, 923–935 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Sharova, N., Swingler, C., Sharkey, M. & Stevenson, M. Macrophages archive HIV-1 virions for dissemination in trans. EMBO J. 24, 2481–2489 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Troisfontaines, P. & Cornelis, G. R. Type III secretion: more systems than you think. Physiology (Bethesda) 20, 326–339 (2005).

    CAS  Google Scholar 

  96. Pelkmans, L. et al. Genome-wide analysis of human kinases in clathrin- and caveolae/raft-mediated endocytosis. Nature 436, 78–86 (2005). Using RNAi screening, this study shows the differential requirement for kinases in clathrin-mediated versus caveolae-mediated endocytosis.

    CAS  PubMed  Google Scholar 

  97. Perret, E., Lakkaraju, A., Deborde, S., Schreiner, R. & Rodriguez-Boulan, E. Evolving endosomes: how many varieties and why? Curr. Opin. Cell Biol. 17, 423–434 (2005).

    CAS  PubMed  Google Scholar 

  98. Stinchcombe, J., Bossi, G. & Griffiths, G. M. Linking albinism and immunity: the secrets of secretory lysosomes. Science 305, 55–59 (2004).

    CAS  PubMed  Google Scholar 

  99. Andrews, N. W. Regulated secretion of conventional lysosomes. Trends Cell Biol. 10, 316–321 (2000).

    CAS  PubMed  Google Scholar 

  100. Raiborg, C. et al. Hrs sorts ubiquitinated proteins into clathrin-coated microdomains of early endosomes. Nature Cell Biol. 4, 394–398 (2002).

    CAS  PubMed  Google Scholar 

  101. Urbe, S. et al. The UIM domain of Hrs couples receptor sorting to vesicle formation. J. Cell Sci. 116, 4169–4179 (2003).

    CAS  PubMed  Google Scholar 

  102. Raiborg, C., Bache, K. G., Mehlum, A., Stang, E. & Stenmark, H. Hrs recruits clathrin to early endosomes. EMBO J. 20, 5008–5021 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Lloyd, T. E. et al. Hrs regulates endosome membrane invagination and tyrosine kinase receptor signaling in Drosophila. Cell 108, 261–269 (2002).

    CAS  PubMed  Google Scholar 

  104. Bache, K. G., Brech, A., Mehlum, A. & Stenmark, H. Hrs regulates multivesicular body formation via ESCRT recruitment to endosomes. J. Cell Biol. 162, 435–442 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Kobayashi, T. et al. Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport. Nature Cell Biol. 1, 113–118 (1999).

    CAS  PubMed  Google Scholar 

  106. Matsuo, H. et al. Role of LBPA and Alix in multivesicular liposome formation and endosome organization. Science 303, 531–534 (2004).

    CAS  PubMed  Google Scholar 

  107. Odorizzi, G., Katzmann, D. J., Babst, M., Audhya, A. & Emr, S. D. Bro1 is an endosome-associated protein that functions in the MVB pathway in Saccharomyces cerevisiae. J. Cell Sci. 116, 1893–1903 (2003).

    CAS  PubMed  Google Scholar 

  108. Luhtala, N. & Odorizzi, G. Bro1 coordinates deubiquitination in the multivesicular body pathway by recruiting Doa4 to endosomes. J. Cell Biol. 166, 717–729 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Journet, L., Hughes, K. T. & Cornelis, G. R. Type III secretion: a secretory pathway serving both motility and virulence (review). Mol. Membr. Biol. 22, 41–50 (2005).

    CAS  PubMed  Google Scholar 

  110. Christie, P. J., Atmakuri, K., Krishnamoorthy, V., Jakubowski, S. & Cascales, E. Biogenesis, architecture, and function of bacterial type IV secretion systems. Annu. Rev. Microbiol. 59, 451–485 (2005).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We apologize to those whose studies could not be mentioned due to space constraints. Support was from the Swiss National Science Foundation (to J.G. and F.G.v.d.G.), National Institute of Health (to F.G.v.d.G.), Howard Hughes Medical Institute (to F.G.v.d.G.) and the International Human Frontier Science Program (to J.G.).

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Jean Gruenberg's homepage

F. Gisou van der Goot's homepage

Glossary

Caveolae

Flask-shaped invaginations of the plasma membrane that are coated with the protein caveolin and are endocytosed in a clathrin-independent manner.

Endosomal carrier vesicles

Transport intermediates between early and late endosomes. They are multivesicular and are therefore also called multivesicular bodies (MVBs).

Mannose-6-phosphate (Man6P) receptors

The receptors that carry lysosomal enzymes that harbour a mannose-6-phosphate moiety to lysosomes.

Major histocompatibility complexes (MHC) class II

Immune complexes that present peptides, which are derived from extracellular antigens, to T cells.

Toll-like receptors

Type I transmembrane proteins that recognize perpetual infectious threat and activate innate responses.

Innate immunity

Nonspecific mechanisms by which pathogens are recognized by cells.

Adaptive immune response

A specific immune response to a given antigen that includes antibody production and the selection of T cells.

MHC class II compartment

A late endosomal compartment that is present in professional antigen-presenting cells and that has specific functions that are distinct from protein degradation. They are enriched in MHC class II proteins and other molecules that are involved in peptide processing, loading and editing and localize to the compartment where most antigen processing and peptide loading occurs.

Exosomes

A term to describe intralumenal vesicles from multivesicular endosomes when they are secreted into the extracellular medium upon fusion of the organelle with the plasma membrane.

Phagosome

The membrane bound compartment that results from the phagocytosis of large particles.

Listeriosis

A rare bacterial infection that is acquired by eating undercooked infected meat or from proximity to infected live animals.

Salmonellosis

Food-borne infection with Salmonella species, which results in diarrhoea, fever and abdominal cramps.

Brucellosis

Infection with Brucella species that is also called Malta or Mediterranean fever. It frequently causes abortions in animals and remittent fever in humans.

Cyclodextrins

Compounds that contain Dglucose units that are joined through α 1–4 linkages in such a way as to form a ring.

Auxotroph

A microorganism that is unable to synthesize a particular organic compound that is required for its growth.

Dendritic cell

The most antigen-presenting cell of the human body.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gruenberg, J., van der Goot, F. Mechanisms of pathogen entry through the endosomal compartments. Nat Rev Mol Cell Biol 7, 495–504 (2006). https://doi.org/10.1038/nrm1959

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1959

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing