The Effects of TLR Activation on T-Cell Development and Differentiation

Figure 6

TRIF signal pathway. In TLR1-TLR13, TRIF is the sole adaptor of TLR3 and also an adjunct adaptor of TLR4. Here, the TLR3-TRIF signal is illustrated as an example of TRIF pathway. dsRNA that is internalized in endosome binds to TLR3, which possesses two dsRNA binding sites near the N-terminus and C-terminus, respectively. When combined with dsRNA, a sole dsRNA molecule associates two TLR3 molecules through four dsRNA binding sites in an “m” shape. TLR3 TIR domain combines with the TIR domain of TRIF. The interaction of TRIF with RIP1 or TRAF6 and Peli1 results in polyubiquitination of RIP1, the latter binds ubiquitin receptors TAB2 and TAB3 which activates TAK1. Activated TAK1 induces phosphorylation of IKK complex composed of IKKα and IKKβ and NEMO. This results in the degradation of IκB which ultimately causes the nuclear translocation of NF-κB to activate the specific gene promoter A20. TAK1 also interacts with JNK and p38 to activate c-JUN and ATF2. This results in the activation of the AP-1 transcription factors family. TRIF also activates TBK1 and IKKε through NAP1 inducing phosphorylation and nuclear translocation of IRF3 culminating in IFN-β production. TRAF3 binds with the TBK1/IKKε complex inducing IRF3 activation. Combination of TRIF results in phosphorylation of Tyr759 and Tyr858 in the TLR3 TIR domain which subsequently induces the phosphorylation and degradation of IκB leading to NF-κB release. Phosphorylated Tyr759 recruits PI3K and phosphorylates kinase Akt and activates nucleic IRF3. Tyrosine kinase c-Src also plays a role in Akt activation. The unique signaling of TRIF is that it interacts with FADD through RIP1 and activates procaspase-8 to initiate cell apoptosis.