Figure 5.

MyD88-independent TLR signaling. Particular TLRs, like TLR3 and TLR4, can initiate MyD88-independent signaling. Receptor activation leads to the association of TRIF (TIR-domain-containing adaptor protein inducing IFN-β) protein. Specific to TLR4 signaling, the adaptor protein TRAM (TRIF-related adaptor molecule) also associates with the receptor to facilitate TRIF binding. As a result of TRIF binding, downstream NF-κB-directed transcription occurs along with IFN-α/β production. Although the exact signaling chronology is undetermined, it is known that two non-canonical IKKs (inhibitor of NF-κB kinase complex), IKKε and TBK1 (TANK-binding kinase 1) are activated. As a result, theses IKKs can initiate both NF-κB and IRF-3 (interferon-3) activity. In addition to IRF-3, IRF-7 is also known to be activated in the independent pathway leading to IFN-α/β production.