The Toll/IL-1 Receptor Adaptor Family - Review


Recognition of pathogens by Toll-like receptors (TLRs) triggers innate immune responses through signaling pathways mediated by Toll/interleukin 1 receptor (TIR) domain containing adaptors. To date, four adaptor proteins have been well characterized, and have been named MyD88, TIRAP/Mal (TIR domain-containing adaptor protein, or MyD88 adaptor-like), TRIF/TICAM1 (TIR-domain-containing adaptor inducing interferon-beta, or TIR-containing adaptor molecule 1) and TRAM/TICAM2/TIRP (TRIF-related adaptor molecule, TIR-containing adaptor molecule 2, or TIR-containing protein). A fifth adaptor has been recently identified, termed SARM1 for sterile alpha motif (SAM) and Armadillo motif (ARM) domain-containing protein[1]. However its function in TLR signaling remains unclear.

TLR signaling consists of at least two distinct pathways: a MyD88-dependent pathway that leads to the production of inflammatory cytokines, and a MyD88-independent pathway associated with the stimulation of IFN-β and the maturation of dendritic cells. The MyD88-dependent pathway is common to all TLRs as MyD88-deficient mice are unable to produce inflammatory cytokines in response to all TLR ligands[2].

However, differences between signaling pathways induced by individual TLRs are emerging, with both TLR4 and TLR2 signaling requiring the adaptor TIRAP/Mal, which may account for the specificity of MyD88-dependent pathways[3]. Although cytokine production in response to the TLR4 ligand LPS is completely abolished in MyD88- or TIRAP-deficient mice, production of IFN-β is still observed. This response is mediated mainly by the adaptor TRIF/TICAM-1 which also plays a critical role in TLR3 signaling[4]. TLR3 recognizes double-stranded RNA (dsRNA) and induces the production of IFN-β through the MyD88-independent pathway. A dominant-negative form of TRIF inhibits TLR3-dependent activation of the IFN-β promoter suggesting that TRIF is a key adaptor in the MyD88-independent pathway.

TRAM/TICAM-2 is another adaptor molecule involved in the MyD88-independent pathway that has been recently characterized[5]. In response to LPS stimulation, TRAM physically bridges TLR4 and TRIF transmitting LPS-induced signaling to TRIF which in turn triggers the production of IFN-β[6]. TRAM function is restricted to the TLR4 pathway, as TRAM-deficient mice are defective in cytokine production in response to the TLR4 ligand LPS but not to other TLR ligands[7].

1. O'Neill LA. et al., 2003. The Toll-IL-1 receptor adaptor family grows to five members. Trends Immunol. 24(6):286-90. Review.
2. Adachi O. et al., 1998. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity. 9(1):143-50.
3. Horng T. et al., 2002. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature. 420(6913):329-33.
4. Yamamoto M. et al., 2002. Cutting edge: a novel Toll/IL-1 receptor domain-containing adaptor that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol. 169(12):6668-72.
5. Fitzgerald KA. et al., 2003. LPS-TLR4 Signaling to IRF-3/7 and NF-{kappa}B Involves the Toll Adapters TRAM and TRIF. J Exp Med. 198(7):1043-1055.
6. Oshiumi H. et al., 2003. TICACM-2: a bridging adaptor recruiting to Toll-like receptor 4 TICAM-1 that induces interferon-beta. J Biol Chem. Sep 30 (Ahead of print).
7. Yamamoto M. et al., 2003. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol. Oct 1 (Ahead of print).

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