Molecular mechanisms that control TLR signaling specificities are obscure at present and need to be elucidated further. Indeed, it is difficult to explain how putative ligand-recognition motifs within the leucine-rich, N-terminal domains enable surprisingly broad TLRs ligand specificities, especially evident for TLR2 and TLR4. In addition, no compelling evidence is available for direct agonist binding by various TLRs. However, TLR-mediated signaling can be blocked by antibodies raised against the N-terminal region of the respective TLRs (Flo et al. 2002; Uehori et al. 2003), and mutations in the extracellular region impair TLR signaling and are associated with infectious and autoimmune diseases (see below). Thus, it is plausible that TLRs respond to PAMPs presented by various accessory molecules primarily by engagement of their ectodomain. Vogel et al. (2003) proposed that interaction of different combinations of adapter molecules and kinases with individual TLRs yields distinct signaling complexes capable of activating different signaling cascades (e.g., distinct repertoires of cytokines and other proinflammatory genes). For instance, TIRAP/MAL and TRAM were reported to be constitutively associated with TLR4, and LPS stimulation triggers recruitment of TRIF to TRAM and MyD88 to TIRAP/MAL. This was proposed to create a signaling platform for downstream kinases and adapters, leading to the recruitment of IRAK-4 and IRAK-1 to MyD88, while TBK-1 and IKKe are recruited to TRIF, kinase activation, and signaling for the full spectrum of MyD88-dependent and MyD88-independent pathways. In contrast, PAMP-mediated engagement of TLR2 triggers its association with MyD88 and TIRAP/MAL, but not TRIF/TRAM. As a result, TLR2-mediated signaling activates the MyD88-dependent pathway only and fails to trigger activation of IRF-3, STAT-1 phosphorylation, and induction of IFN-P or IFN-P-dependent genes (Vogel et al. 2003). Thus, the response to specific TLR agonists is constrained by two sets of specificities: through the N-terminal domain, sensing of specific PAMPs (without or with co-receptors) initiates TLR oligomerization and activation, while engagement of different combinations of adapter molecules through receptor/adapter TIR-TIR interactions at the intracellular TLR region leads to recruitment of the distinct combinations of enzymes and substrates associated with the specific receptor/adapter complex.
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