TLR signaling pathways. Upon respective ligands binding, TLRs form homo- or heterodimers and recruit one or more adaptor proteins, namely, MyD88, MAL/TIRAP, TRIF, or TRAM, to the cytoplasmic domains of the receptors through homophilic interactions between Toll/IL-1 receptor (TIR) domains present in each receptor and each adaptor. All TLRs with exception of TLR3 use the common MyD88-dependent pathway. TIRAP acts as a bridge to recruit MyD88 to TLR2 and TLR4 signaling, whereas TRIF is used in TLR3 signaling and, in association with TRAM, in TLR4 signaling. In MyD88-dependent pathway, MyD88 associates with IRAK4, IRAK1, and/or IRAK2. IRAK4 in turn phosphorylates IRAK1 and/or IRAK2 and promotes their association with TRAF6, which serves as a platform to recruit and activate the kinase TAK1. Activated TAK1 activates the IKK complex, composed of IKKα, IKKβ, and NEMO (IKKγ), which in turn catalyzes phosphorylation and subsequent degradation of IκB. IκB degradation lets NF-κB (i.e., p50/p65) free to translocate from the cytoplasma to the nucleus, where it activates multiple gene expression. The transcription factor IRF7 is activated as the downstream signaling molecule of TLR 7, 8, and 9. It is directly phosphorylated by IRAK1 and then translocates into the nucleus to induce the expression of type I IFN and IFN-inducible genes. In the Trif-dependent pathway, Trif interacts with TRAF3 to activate TBK1 and IKKi, resulting in the dimerization and activation of IRF3, which then translocates into the nucleus activating the transcription of type I IFN and IFN-inducible genes.
