Immune response - TLR3 and TLR4 induce TICAM1-specific signaling pathway

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Role of TLRs 3 and 4 in cell antiviral response: TICAM1-specific signaling pathways

Toll-like receptors (TLR) initiate signaling cascades through recognition of a variety of microbial components, thus serving as an important link between innate and adaptive immune responses. Each TLR recognizes distinct ligands by means of its leucine-rich repeats and elicits different, but often overlapping immune responses [1].

TLR3-induced signaling pathways are triggered by binding of virus-derived double-stranded RNA [1], whereas TLR4 becomes activated after binding to number of bacterial cell wall components: Lipopolysaccharide (LPS) [1], Pulmonary surfactant-associated protein A (PSAP) [2], Paclitaxel [3], Fibronectin [4], Pneumolysin [5].

Although Myeloid differentiation primary response gene 88 (MyD88)-dependent signaling pathway is common for all TLRs, TLR3- and TLR4-induced activation of the transcription factor nuclear factor kappa B (NF-kB) can be mediated by some alternative adaptors. It can be activated by TLR3 ligands via Toll-like receptor adaptor molecule 1 (TRIF (TICAM1)) [1]. TLR4 signaling can also be mediated by TRIF (TICAM1), which binds to TLR4 adaptor Toll-like receptor adaptor molecule 2 (TRAM) [6]. In addition TLRs are able to induce autophagy through TRIF (TICAM1) - Beclin 1 interaction [7]. TLR4 activates NF-kB independently of TRIF (TICAM1) through its other adaptor, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP (Mal)) [8]. TRIF (TICAM1)-dependent NF-kB activation is mediated either by TNF receptor-associated factor 6 (TRAF6) or by Receptor TNFRSF-interacting serine-threonine kinase 1 (RIPK1)-induced kinase cascade [1]. Moreover, TRIF (TICAM1) causes activation of transcription factor Interferon regulatory factor 3 (IRF3) [9]. Both IRF3 and NF-kB regulate expression of such proinflammatory molecules as Interferon alpha and beta (IFN-alpha and IFN-beta), thus mediating the antiviral action of interferon.

References:

  1. Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, Tschopp J
    RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nature immunology 2004 May;5(5):503-7
  2. Guillot L, Balloy V, McCormack FX, Golenbock DT, Chignard M, Si-Tahar M
    Cutting edge: the immunostimulatory activity of the lung surfactant protein-A involves Toll-like receptor 4. Journal of immunology (Baltimore, Md. : 1950) 2002 Jun 15;168(12):5989-92
  3. Takeuchi O, Akira S
    Toll-like receptors; their physiological role and signal transduction system. International immunopharmacology 2001 Apr;1(4):625-35
  4. Lee J, Chuang TH, Redecke V, She L, Pitha PM, Carson DA, Raz E, Cottam HB
    Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. Proceedings of the National Academy of Sciences of the United States of America 2003 May 27;100(11):6646-51
  5. Malley R, Henneke P, Morse SC, Cieslewicz MJ, Lipsitch M, Thompson CM, Kurt-Jones E, Paton JC, Wessels MR, Golenbock DT
    Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proceedings of the National Academy of Sciences of the United States of America 2003 Feb 18;100(4):1966-71
  6. Oshiumi H, Sasai M, Shida K, Fujita T, Matsumoto M, Seya T
    TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta. The Journal of biological chemistry 2003 Dec 12;278(50):49751-62
  7. Shi CS, Kehrl JH
    MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages. The Journal of biological chemistry 2008 Nov 28;283(48):33175-82
  8. Jefferies CA, Doyle S, Brunner C, Dunne A, Brint E, Wietek C, Walch E, Wirth T, O'Neill LA
    Bruton's tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. The Journal of biological chemistry 2003 Jul 11;278(28):26258-64
  9. Jiang Z, Mak TW, Sen G, Li X
    Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta. Proceedings of the National Academy of Sciences of the United States of America 2004 Mar 9;101(10):3533-8

  1. Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, Tschopp J
    RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nature immunology 2004 May;5(5):503-7
  2. Guillot L, Balloy V, McCormack FX, Golenbock DT, Chignard M, Si-Tahar M
    Cutting edge: the immunostimulatory activity of the lung surfactant protein-A involves Toll-like receptor 4. Journal of immunology (Baltimore, Md. : 1950) 2002 Jun 15;168(12):5989-92
  3. Takeuchi O, Akira S
    Toll-like receptors; their physiological role and signal transduction system. International immunopharmacology 2001 Apr;1(4):625-35
  4. Lee J, Chuang TH, Redecke V, She L, Pitha PM, Carson DA, Raz E, Cottam HB
    Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. Proceedings of the National Academy of Sciences of the United States of America 2003 May 27;100(11):6646-51
  5. Malley R, Henneke P, Morse SC, Cieslewicz MJ, Lipsitch M, Thompson CM, Kurt-Jones E, Paton JC, Wessels MR, Golenbock DT
    Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proceedings of the National Academy of Sciences of the United States of America 2003 Feb 18;100(4):1966-71
  6. Oshiumi H, Sasai M, Shida K, Fujita T, Matsumoto M, Seya T
    TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta. The Journal of biological chemistry 2003 Dec 12;278(50):49751-62
  7. Shi CS, Kehrl JH
    MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages. The Journal of biological chemistry 2008 Nov 28;283(48):33175-82
  8. Jefferies CA, Doyle S, Brunner C, Dunne A, Brint E, Wietek C, Walch E, Wirth T, O'Neill LA
    Bruton's tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. The Journal of biological chemistry 2003 Jul 11;278(28):26258-64
  9. Jiang Z, Mak TW, Sen G, Li X
    Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta. Proceedings of the National Academy of Sciences of the United States of America 2004 Mar 9;101(10):3533-8

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