TLR structure and signaling. (A) Toll-like receptors and interleukin-1 receptors have a conserved cytoplasmic domain, that is known as the Toll/IL-1 R domain. The TIR domain is characterized by the presence of three highly homologous regions (known as boxes 1, 2 and 3). Despite the similarity of the cytoplasmic domains of these molecules, their extracellular regions differ markedly: TLRs have tandem repeats of leucine-rich regions (known as leucine rich repeats, LRR), whereas IL-1 Rs have three immunoglobulin (Ig)-like domains. (B) Stimulation of TLRs triggers the association of MyD88, which in turn recruits IRAK4, thereby allowing the association of IRAK1. IRAK4 then induces the phosphorylation of IRAK1. TRAF6 is also recruited to the receptor complex, by associating with phosphorylated IRAK1. Phosphorylated IRAK1 and TRAF6 then dissociate from the receptor and form a complex with TAK1, TAB1 and TAB2 at the plasma membrane (not shown), which induces the phosphorylation of TAB2 and TAK1. IRAK1 is degraded at the plasma membrane, and the remaining complex (consisting of TRAF6, TAK1, TAB1 and TAB2) translocates to the cytosol, where it associates with the ubiquitin ligases UBC13 and UEV1A. This leads to the ubiquitylation of TRAF6, which induces the activation of TAK1. TAK1, in turn, phosphorylates both MAP kinases and the IKK complex, which consists of IKK-α, IKK-β and IKK-γ (also known as IKK1, IKK2, NEMO, respectively). The IKK complex then phosphorylates IκB, which leads to its ubiquitylation and subsequent degradation. This allows NF-κB to translocate to the nucleus and induce the expression of its target genes. (C) The MyD88 dependent pathway is used by TLR1, TLR2, TLR4, TLR5, TLR6, TLR7 and TLR9. TIRAP, a second TIR-domain-containing adaptor protein, is involved in the MyD88-dependent signaling pathway through TLR2 and TLR4. By contrast, TLR3- and TLR4-mediated activation of interferon (IFN)-regulatory factor 3 (IRF3) and the induction of IFN-β occur in a MyD88-independent manner. As shown, a third TIR-domain-containing adaptor, TRIF, is essential for the MyD88-independent pathway through TLR3 and TLR4. TRAM, A fourth TIR-domain containing adaptor, is specific to the TLR4-mediated, MyD88-independent/TRIF-dependent pathway. TRIF mediates the activation of the non-canonical IKKs, IKK-ε and TBK1, as well as MAP kinase. Note TLR3 is predominately located within endosomes (not illustrated). (Modified from Akira S, Takeda K. Toll like receptor signalling. Nat Rev Immunol 2004: 7; 499–511)
