Adaptor proteins mediating the signaling of TLR receptors. TLR signaling is mediated via two pathways: MyD88-dependent and TRIF-dependent pathway. In the MyD88-dependent pathway, TIRAP mediates the interaction of MyD88 with TLR2/4 for the initiation of the signaling cascade. The adaptor proteins SOCS-1, IRAK1/4, CLIP170, and Triad3A inhibit the function of TIRAP. MyD88 recruits IRAK-1, which will be phosphorylated and bind to TRAF6. Once activated, TRAF6 acts as an E3 ubiquitin ligase, ubiquitinates, and activates NEMO, IKKα, and IKKβ to induce the phosphorylation of IκB and subsequent dissociation from NF-κB, resulting in the nuclear translocation of NF-κB. SOCS-1, Ub-DOK-3, NLRC5, and IRF7 inhibit the activation of IKKα/β, downregulating the NF-κB pathway. In parallel, MyD88 induces the p38, MAPK, and JNK/ERK signaling for the activation and translocation of AP-1 in the nucleus. In the TRIF-dependent pathway, TRIF indirectly interacts with TLR4 via TRAM and activates IRF3 via TRAF3, which translocates in the nucleus and induces the expression of IFN-β. The role of TRIF is inhibited by SARM. DAP12 associates with TREM2 upon stimulation and induces the phosphorylation and translocation of DOK-3 on the cell membrane, resulting in the inhibition of MAPK and ERK pathways. Meanwhile, ubiquitin-mediated degradation of DOK-3 leads to SOS1 degradation and inhibition of ERK pathway. TLR2/4, Toll-like receptor 2/4; TIRAP, TIR domain-containing adaptor protein; MyD88, myeloid differentiation 88; IRAK-1/4/M, interleukin-1 receptor-associated kinase 1/4/M; TRAF3/6, TNF receptor associated factor 3/6; NEMO, nuclear factor-κB essential modulator; IKKα/β, inhibitory kappa B kinase α/β; NF-κB, nuclear factor-κB; SOCS-1, suppressor of cytokine signaling-1; CLIP170, cytoplasmic linker protein 170; NLRC5, NOD-like receptor family caspase recruitment domain family domain containing 5; DOK-3, downstream of kinase 3; DAP12, DNAX-activating protein of 12 kDa; Grb2, growth factor receptor-bound protein 2; SOS1, Son of sevenless homolog 1; TRIF, TIR domain-containing adaptor-inducing interferon-β; TRAM, TRIF-related adaptor molecule; SARM, Sterile α and Armadillo motif-containing protein; DAB2, Disabled-2; IRF3/5/7, interferon regulatory factor 3/5/7; AP-1, activator protein 1; IFN-β, interferon-β; NLRs, nucleotide-binding oligomerization domain (NOD)–leucine-rich repeat (LRR)-containing receptors; CLRs, C-type lectin receptors. Created with BioRender.com
