| TLR9 belongs to the Toll-like receptor family of pattern recognition receptors that orchestrate innate immune responses to microbial nucleic acids. Expressed primarily in plasmacytoid dendritic cells, B cells, and macrophages, TLR9 resides in the endoplasmic reticulum until ligand engagement triggers endosomal trafficking where cathepsin-mediated cleavage generates an active N-terminal ligand-binding fragment while retaining the C-terminal TIR signaling domain. Unmethylated CpG DNA motifs bind within the LRR horseshoe structure, inducing receptor dimerization and high-affinity recruitment of the MyD88 adaptor protein; this assembles the myddosome complex with IRAK4 kinase phosphorylating IRAK1/2, which then activates TRAF6 auto-ubiquitination. TRAF6 recruits the TAK1 kinase complex that splits signaling into two arms—activation of IKK leading to NF-κB nuclear translocation and transcription of TNF-α, IL-6, and IL-12, alongside MAPK cascades stabilizing AP-1 for enhanced cytokine production. In plasmacytoid DCs, a parallel pathway incorporates TRAF3 with IKKα to phosphorylate IRF7, driving robust type I interferon responses. UNC93B1 chaperones TLR9 trafficking, while AP-3 complex directs interferon-competent signaling to lysosome-related organelles distinct from early endosomal NF-κB compartments. TLR9 coordinates antiviral states through interferon-stimulated genes, matures antigen-presenting cells for adaptive immunity, and enhances phagocytosis via ROS production. Self-DNA immune complexes activate TLR9 in systemic lupus erythematosus, fueling autoreactive B cell expansion and interferon-driven pathology. |
