Investigating the TLR3 Signaling Dynamics

  • Kumar Selvarajoo
Part of the Systems Biology book series (SYSTBIOL, volume 3)


Along with TLR-7, -8, and -9, TLR3 is an intracellular member of the Toll-like receptor (TLR) superfamily (see Chap. 3). It plays a crucial role in the mammalian innate immune response against viral attacks by recognizing double-stranded RNA (dsRNA) or its synthetic analogue polyinosinic-polycytidylic acid (poly (I:C)). TLR3 is expressed in several cell types including macrophages, murine embryonic fibroblasts (MEFs), and dendritic cells; however, it has not been detected in B cells, T cells, and NK cells. In contrast to all other TLRs, the TLR3 response is independent of the adaptor protein MyD88. The specificity of the TLR3 response possibly results from the occurrence of an alanine residue in a critical region of its cytoplasmic domain, in contrast to the proline residue utilized by MyD88 found in other TLRs. Thus, TLR3 initiates its response depending only on the adaptor protein TRIF and does not involve TRAM.


TLR3 Signaling Response Rule Intermediary Step Murine Embryonic Fibroblast Viral Attack 
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.


  1. 1.
    Boehme KW, Compton T (2004) Innate sensing of viruses by Toll-like receptors. J Virol 78:7867–7873PubMedCrossRefGoogle Scholar
  2. 2.
    Krishnan J, Selvarajoo K, Tsuchiya M, Lee G, Choi S (2007) Toll-like receptor signal transduction. Exp Mol Med 39:421–438PubMedCrossRefGoogle Scholar
  3. 3.
    Gohda J, Matsumura T, Inoue J (2004) Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling. J Immunol 173:2913–2917PubMedGoogle Scholar
  4. 4.
    Chen NJ, Chio II, Lin WJ, Duncan G, Chau H, Katz D, Huang HL, Pike KA, Hao Z, Su YW, Yamamoto K, de Pooter RF, Zúñiga-Pflücker JC, Wakeham A, Yeh WC, Mak TW (2008) Beyond tumor necrosis factor receptor: TRADD signaling in Toll-like receptors. Proc Natl Acad Sci USA 105:12429–12434PubMedCrossRefGoogle Scholar
  5. 5.
    Jiang Z, Mak TW, Sen G, Li X (2004) Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta. Proc Natl Acad Sci USA 101:3533–3538PubMedCrossRefGoogle Scholar
  6. 6.
    Pobezinskaya YL, Kim YS, Choksi S, Morgan MJ, Li T, Liu C, Liu Z (2008) The function of TRADD in signaling through tumor necrosis factor receptor 1 and TRIF-dependent Toll-like receptors. Nat Immunol 9:1047–1054PubMedCrossRefGoogle Scholar
  7. 7.
    Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, Takeuchi O, Takeda K, Akira S (2003) TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 4:1144–1150PubMedCrossRefGoogle Scholar
  8. 8.
    Hoebe K, Du X, Georgel P, Janssen E, Tabeta K, Kim SO, Goode J, Lin P, Mann N, Mudd S, Crozat K, Sovath S, Han J, Beutler B (2003) Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424:743–748PubMedCrossRefGoogle Scholar
  9. 9.
    Helmy M, Gohda J, Inoue J, Tomita M, Tsuchiya M, Selvarajoo K (2009) Predicting novel features of Toll-like receptor 3 signaling in macrophages. PLoS One 4:e4661PubMedCrossRefGoogle Scholar
  10. 10.
    Liu L, Botos I, Wang Y, Leonard JN, Shiloach J, Segal DM, Davies DR (2008) Structural basis of Toll-like receptor 3 signaling with double-stranded RNA. Science 320:379–381PubMedCrossRefGoogle Scholar
  11. 11.
    Itoh K, Watanabe A, Funami K, Seya T, Matsumoto M (2008) The clathrin-mediated endocytic pathway participates in dsRNA-induced IFN-beta production. J Immunol 181:5522–5529PubMedGoogle Scholar
  12. 12.
    Carpenter S, Wochal P, Dunne A, O’Neill LA (2011) Toll-like receptor 3 (TLR3) signaling requires TLR4 Interactor with leucine-rich repeats (TRIL). J Biol Chem 286:38795–38804PubMedCrossRefGoogle Scholar
  13. 13.
    Garcia-Cattaneo A, Gobert FX, Müller M, Toscano F, Flores M, Lescure A, Del Nery E, Benaroch P (2012) Cleavage of Toll-like receptor 3 by cathepsins B and H is essential for signaling. Proc Natl Acad Sci USA 109:9053–9058PubMedCrossRefGoogle Scholar
  14. 14.
    Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis e Sousa C, Matsuura Y, Fujita T, Akira S (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105PubMedCrossRefGoogle Scholar
  15. 15.
    Takeuchi O, Akira S (2008) MDA5/RIG-I and virus recognition. Curr Opin Immunol 20:17–22PubMedCrossRefGoogle Scholar
  16. 16.
    Lamkanfi M, D’hondt K, Vande Walle L, van Gurp M, Denecker G, Demeulemeester J, Kalai M, Declercq W, Saelens X, Vandenabeele P (2005) A novel caspase-2 complex containing TRAF2 and RIP1. J Biol Chem 280:6923–6932PubMedCrossRefGoogle Scholar
  17. 17.
    Oganesyan G, Saha SK, Guo B, He JQ, Shahangian A, Zarnegar B, Perry A, Cheng G (2006) Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 439:208–211PubMedCrossRefGoogle Scholar
  18. 18.
    Su X, Li S, Meng M, Qian W, Xie W, Chen D, Zhai Z, Shu HB (2006) TNF receptor-associated factor-1 (TRAF1) negatively regulates Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-mediated signaling. Eur J Immunol 36:199–206PubMedCrossRefGoogle Scholar
  19. 19.
    Miggin SM, O’Neill LA (2006) New insights into the regulation of TLR signaling. J Leukoc Biol 80:220–226PubMedCrossRefGoogle Scholar
  20. 20.
    Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, Tschopp J (2004) RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nat Immunol 5:503–507PubMedCrossRefGoogle Scholar
  21. 21.
    Meylan E, Tschopp J (2005) The RIP kinases: crucial integrators of cellular stress. Trends Biochem Sci 30:151–159PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Kumar Selvarajoo
    • 1
  1. 1.Institute for Advanced BiosciencesKeio UniversityTsuruokaJapan

Personalised recommendations