The Journey of Toll-like Receptors in the Cell

  • Øyvind Halaas
  • Harald Husebye
  • Terje Espevik1
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 598)


Endoplasmic Reticulum Early Endosome Late Endosome Clathrin Heavy Chain FYVE Domain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Ahmad-Nejad, P., Hacker, H., Rutz, M., Bauer, S., Vabulas, R.M. and Wagner, H. (2002) Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments. Eur. J. Immunol. 32, 1958-1968.PubMedCrossRefGoogle Scholar
  2. Blander, J.M. and Medzhitov, R. (2006) Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature 440, 808-812.PubMedCrossRefGoogle Scholar
  3. Bohnhorst, J., Rasmussen, T., Moen, S.H., Flottum, M., Knudsen, L., Borset, M., Espevik, T. and Sundan, A. (2006) Toll-like receptors mediate proliferation and survival of multiple myeloma cells. Leukemia 20, 1138-1144.PubMedCrossRefGoogle Scholar
  4. Bonifacino, J.S. and Traub, L.M. (2003) Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu. Rev Biochem. 72, 395-447.PubMedCrossRefGoogle Scholar
  5. Bright, N.A., Gratian, M.J. and Luzio, J.P. (2005) Endocytic delivery to lysosomes mediated by concurrent fusion and kissing events in living cells. Curr. Biol. 15, 360-365.PubMedCrossRefGoogle Scholar
  6. Chen, L.Y., Zuraw, B.L., Zhao, M., Liu, F.T., Huang, S. and Pan, Z.K. (2003) Involvement of protein tyrosine kinase in Toll-like receptor 4-mediated NF-kappa B activation in human peripheral blood monocytes. Am J Physiol Lung Cell Mol Physiol 284, L607-L613.PubMedGoogle Scholar
  7. Choe, J., Kelker, M.S. and Wilson, I.A. (2005) Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science 309, 581-585.PubMedCrossRefGoogle Scholar
  8. Chuang, T.H. and Ulevitch, R.J. (2004) Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors. Nat Immunol 5, 495-502.PubMedCrossRefGoogle Scholar
  9. Di Paolo, G. and De Camilli, P. (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651-657.PubMedCrossRefGoogle Scholar
  10. Edelson, B.T. and Unanue, E.R. (2002) MyD88-dependent but Toll-like receptor 2-independent innate immunity to Listeria: no role for either in macrophage listericidal activity. J. Immunol. 169, 3869-3875.PubMedGoogle Scholar
  11. Feng, C.G., Scanga, C.A., Collazo-Custodio, C.M., Cheever, A.W., Hieny, S., Caspar, P. and Sher, A. (2003) Mice lacking myeloid differentiation factor 88 display profound defects in host resistance and immune responses to Mycobacterium avium infection not exhibited by Toll-like receptor 2 (TLR2)- and TLR4-deficient animals. J. Immunol. 171, 4758-4764.PubMedGoogle Scholar
  12. Funami, K., Matsumoto, M., Oshiumi, H., Akazawa, T., Yamamoto, A. and Seya, T. (2004) The cytoplasmic ‘linker region’ in Toll-like receptor 3 controls receptor localization and signaling. Int. Immunol. 16, 1143-1154.PubMedCrossRefGoogle Scholar
  13. Gillooly, D.J., Morrow, I.C., Lindsay, M., Gould, R., Bryant, N.J., Gaullier, J.M., Parton, R.G. and Stenmark, H. (2000) Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells. EMBO J 19, 4577-4588.PubMedCrossRefGoogle Scholar
  14. Gruenberg, J. and Stenmark, H. (2004) The biogenesis of multivesicular endosomes. Nat Rev Mol Cell Biol 5, 317-323.PubMedCrossRefGoogle Scholar
  15. Gruenberg, J. and van der Goot, F.G. (2006) Mechanisms of pathogen entry through the endosomal compartments. Nat. Rev. Mol. Cell Biol. 7, 495-504.PubMedCrossRefGoogle Scholar
  16. Guha, M. and Mackman, N. (2002) The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J. Biol. Chem. 277, 32124-32132.PubMedCrossRefGoogle Scholar
  17. Guillot, L., Medjane, S., Le-Barillec, K., Balloy, V., Danel, C., Chignard, M. and Si-Tahar, M. (2004) Response of human pulmonary epithelial cells to lipopolysaccharide involves Toll-like receptor 4 (TLR4)-dependent signaling pathways: evidence for an intracellular compartmentalization of TLR4. J. Biol. Chem. 279, 2712-2718.PubMedCrossRefGoogle Scholar
  18. Haglund, K., Sigismund, S., Polo, S., Szymkiewicz, I., Di Fiore, P.P. and Dikic, I. (2003) Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat. Cell Biol. 5, 461-466.PubMedCrossRefGoogle Scholar
  19. Hornef, M.W., Normark, B.H., Vandewalle, A. and Normark, S. (2003) Intracellular recognition of lipopolysaccharide by toll-like receptor 4 in intestinal epithelial cells. J. Exp. Med. 198, 1225-1235.PubMedCrossRefGoogle Scholar
  20. Huang, F., Kirkpatrick, D., Jiang, X., Gygi, S. and Sorkin, A. (2006) Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol. Cell 21, 737-748.PubMedCrossRefGoogle Scholar
  21. Husebye, H., Halaas, O., Stenmark, H., Tunheim, G., Sandanger, O., Bogen, B., Brech, A., Latz, E. and Espevik, T. (2006) Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity. EMBO J. 25, 683-692.PubMedCrossRefGoogle Scholar
  22. Johnsen, I.B., Nguyen, T.T., Ringdal, M., Tryggestad, A.M., Bakke, O., Lien, E., Espevik, T. and Anthonsen, M.W. (2006) Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to initiate antiviral signaling. EMBO J. 25, 3335-3346.PubMedCrossRefGoogle Scholar
  23. Kagan, J.C. and Medzhitov, R. (2006) Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell 125, 943-955.PubMedCrossRefGoogle Scholar
  24. Lang, K.S., Recher, M., Junt, T., Navarini, A.A., Harris, N.L., Freigang, S., Odermatt, B., Conrad, C., Ittner, L.M., Bauer, S., Luther, S.A., Uematsu, S., Akira, S., Hengartner, H. and Zinkernagel, R.M. (2005) Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Nat. Med. 11, 138-145.PubMedCrossRefGoogle Scholar
  25. Latz, E., Schoenemeyer, A., Visintin, A., Fitzgerald, K.A., Monks, B.G., Knetter, C.F., Lien, E., Nilsen, N.J., Espevik, T. and Golenbock, D.T. (2004) TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat. Immunol. 5, 190-198.PubMedCrossRefGoogle Scholar
  26. Latz, E., Visintin, A., Lien, E., Fitzgerald, K.A., Monks, B.G., Kurt-Jones, E.A., Golenbock, D.T. and Espevik, T. (2002) Lipopolysaccharide rapidly traffics to and from the golgi apparatus with the toll-like receptor 4-MD-2-CD14 complex in a process that is distinct from the initiation of signal transduction. J. Biol. Chem. 277, 47834-47843.PubMedCrossRefGoogle Scholar
  27. Leifer, C.A., Brooks, J.C., Hoelzer, K., Lopez, J.L., Kennedy, M.N., Mazzoni, A. and Segal, D.M. (2006) Cytoplasmic targeting motifs control localization of toll-like receptor 9. J. Biol. Chem.Google Scholar
  28. Liew, F.Y., Xu, D., Brint, E.K. and O’Neill, L.A. (2005) Negative regulation of toll-like receptor-mediated immune responses. Nat. Rev. Immunol. 5, 446-458.PubMedCrossRefGoogle Scholar
  29. Marshak-Rothstein, A. (2006) Toll-like receptors in systemic autoimmune disease. Nat. Rev. Immunol. 6, 823-835.PubMedCrossRefGoogle Scholar
  30. Means, T.K., Latz, E., Hayashi, F., Murali, M.R., Golenbock, D.T. and Luster, A.D. (2005) Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J. Clin. Invest 115, 407-417.PubMedCrossRefGoogle Scholar
  31. Meusser, B., Hirsch, C., Jarosch, E. and Sommer, T. (2005) ERAD: the long road to destruction. Nat. Cell Biol. 7, 766-772.PubMedCrossRefGoogle Scholar
  32. Nilsen, N., Nonstad, U., Khan, N., Knetter, C.F., Akira, S., Sundan, A., Espevik, T. and Lien, E. (2004) Lipopolysaccharide and double-stranded RNA up-regulate toll-like receptor 2 independently of myeloid differentiation factor 88. J. Biol. Chem. 279, 39727-39735.PubMedCrossRefGoogle Scholar
  33. Nishiya, T., Kajita, E., Miwa, S. and Defranco, A.L. (2005) TLR3 and TLR7 are targeted to the same intracellular compartments by distinct regulatory elements. J. Biol. Chem. 280, 37107-37117.PubMedCrossRefGoogle Scholar
  34. Pasare, C. and Medzhitov, R. (2004) Toll-dependent control mechanisms of CD4 T cell activation. Immunity. 21, 733-741.PubMedCrossRefGoogle Scholar
  35. Rowe, D.C., McGettrick, A.F., Latz, E., Monks, B.G., Gay, N.J., Yamamoto, M., Akira, S., O’Neill, L.A., Fitzgerald, K.A. and Golenbock, D.T. (2006) The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction. Proc. Natl. Acad. Sci. U. S. A 103, 6299-6304.PubMedCrossRefGoogle Scholar
  36. Saitoh, S., Akashi, S., Yamada, T., Tanimura, N., Matsumoto, F., Fukase, K., Kusumoto, S., Kosugi, A. and Miyake, K. (2004) Ligand-dependent Toll-like receptor 4 (TLR4)-oligomerization is directly linked with TLR4-signaling. J. Endotoxin. Res. 10, 257-260.PubMedGoogle Scholar
  37. Sarkar, S.N., Peters, K.L., Elco, C.P., Sakamoto, S., Pal, S. and Sen, G.C. (2004) Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling. Nat. Struct. Mol. Biol. 11, 1060-1067.PubMedCrossRefGoogle Scholar
  38. Schaible, U.E. and Kaufmann, S.H. (2004) Iron and microbial infection. Nat. Rev. Microbiol. 2, 946-953.PubMedCrossRefGoogle Scholar
  39. Stenmark, H., Aasland, R. and Driscoll, P.C. (2002) The phosphatidylinositol 3-phosphate-binding FYVE finger. Febs Letters 513, 77-84.PubMedCrossRefGoogle Scholar
  40. Tabeta, K., Hoebe, K., Janssen, E.M., Du, X., Georgel, P., Crozat, K., Mudd, S., Mann, N., Sovath, S., Goode, J., Shamel, L., Herskovits, A.A., Portnoy, D.A., Cooke, M., Tarantino, L.M., Wiltshire, T., Steinberg, B.E., Grinstein, S. and Beutler, B. (2006) The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat. Immunol. 7, 156-164.PubMedCrossRefGoogle Scholar
  41. Thieblemont, N. and Wright, S.D. (1999) Transport of bacterial lipopolysaccharide to the golgi apparatus. J. Exp. Med. 190, 523-534.PubMedCrossRefGoogle Scholar
  42. Uematsu, S. and Akira, S. (2006) Toll-like receptors and innate immunity. J. Mol. Med.Google Scholar
  43. Venkateswarlu, K., Oatey, P.B., Tavare, J.M. and Cullen, P.J. (1998) Insulin-dependent translocation of ARNO to the plasma membrane of adipocytes requires phosphatidylinositol 3-kinase. Curr. Biol. 8, 463-466.PubMedCrossRefGoogle Scholar
  44. Yarovinsky, F., Zhang, D., Andersen, J.F., Bannenberg, G.L., Serhan, C.N., Hayden, M.S., Hieny, S., Sutterwala, F.S., Flavell, R.A., Ghosh, S. and Sher, A. (2005) TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308, 1626-1629.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Øyvind Halaas
    • 1
    • 2
  • Harald Husebye
    • 1
  • Terje Espevik1
    • 1
  1. 1.Institute of Cancer Research and Molecular MedicineNTNUN-7489 TrondheimNorway
  2. 2.St. Olavs HospitalN-7006 TrondheimNorway

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