The TLR4 agonist MPL has been demonstrated to act primarily by triggering TIR-domain-containing adapter-inducing beta-interferon (TRIF -mediated signaling (36) and TRIF -mediatedin contrasignalingPS, a nonproinflammatory innate immune response, which may be suboptimal for the effective induction of memory CD8+ T-cell activity (36).
The assembly and activation of these adapters ultimately trigger PKCθ activation leading to the translocation of transcription factors such as NF-κB and the production of cytokines (Smith-Garvin et al, 2009).
All TLR/IL-1Rs, with the exception of TLR3, interact with MyD88, an intracellular adapter protein that triggers a signaling cascade that culminates in the expression of inflammatory genes.
This coupling is due to a feed-forward pathway mediated by inducible expression of the rate-limiting signaling adapter, TRAF1, that triggers activation of the noncanonical pathway [ 57].
The C-terminal tail of LMP1 provides docking sites for the recruitment and activation of signaling adapter proteins, which triggers various downstream oncogenic signaling pathways, such as NF-κB, MAPK, PI3K and JAK/STAT pathways [ 5].
Reelin signaling requires binding to receptors of the lipoprotein family, very low density-lipoprotein (VLDLR) and the apolipoprotein E receptor (ApoER2), which triggers tyrosine phosphorylation of the cytoplasmic adapter protein Disabled-1 (Dab1) [35], [36], [36].
The TLRs are composed of an extracellular domain that binds the PAMPs, a signal transmembrane domain and an intracellular domain, designated the TIR domain that binds adapter molecules and that triggers the intracellular cascades leading to the innate immune response.
For debugging purposes, a (one bit) frame start trigger signal is available in a separate port adapter.
Nucleic acid binding to TLR homodimers recruits the adapter proteins TRIF or MyD88 to trigger NF-κB and/or IRF signalling pathways, inducing pro-inflammatory cytokines and type I interferon (IFN) respectively (Blasius & Beutler, 2010).
There is subsequent autophosphorylation of the cytoplasmic tyrosine kinase (TK) domain with the help of adapter proteins (e.g., SHC and GRB-2), which triggers downstream signaling.
