TLR8 (Toll-like receptor 8) is an endosomal receptor that plays a key role in innate and adaptive immunity by recognizing pathogen-associated molecular patterns such as single-stranded nucleic acids from viruses and bacteria. TLR8 is a type I transmembrane protein characterized by an extracellular leucine-rich repeat (LRR) domain, a transmembrane helix, and an intracellular Toll/interleukin-1 receptor (TIR) homology domain. TLR8 is monomeric in the absence of ligands and transforms into an activated dimer form on ligand binding, which allows for dimerization of the intracellular TIR domain and subsequent signaling. TLR8 possess a long inserted loop region (Z-loop), consisting of about 30 amino acid residues, between LRR14 and LRR15, and the processing by proteolytic cleavage at the Z-loop produces functional TLR8 capable of TLR8 dimerization, ligand binding, and signaling in endolysosomes. The uncleaved Z-loop prevents formation of the TLR8 dimer, which is essential for its activation, by preventing the dimerization partner by steric hindrance. In autoinhibited state, Z-loop is sandwiched by LRR8, LRR11-LRR13, and LRR18-LRR19.