Abstract

Toll-like receptors (TLRs) are pattern-recognition receptors that initiate innate immune responses. Among the TLRs, TLR8 (and TLR7) recognizes single-stranded RNA to mediate downstream signals. In recent years, intensive X-ray crystal structural analyses have provided atomic insights into structures of TLR8 complexed with various agonists or antagonists. Here, structural knowledge of the activation and inactivation mechanisms of the ligands is reviewed. In addition, the potential clinical applications of TLR ligands are examined.

Highlights

  • Toll-like receptors (TLRs) are a family of single transmembrane receptors that recognize molecular patterns from microbes or viruses and activate the innate immune system (Fig. 1a)

  • Ten TLRs have been identified in humans, including TLR1, TLR2, TLR4, TLR5 and TLR6, which are located on cell surfaces and mainly recognize the components of bacteria; others, including TLR3, TLR7, TLR8 and TLR9, are located in endosomes and recognize pathogen-derived nucleic acids (Kawai & Akira, 2010)

  • Dimeric structures of TLR8 with or without agonistic synthetic imidazoquinoline compounds (R848, CL097 and CL075) were reported (Figs. 2a and 2b; Tanji et al, 2013). These results demonstrated that TLR8 forms an unliganded dimer state, unlike other TLRs localized on cell surfaces, and is converted into an activated dimer state triggered by ligand binding

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Summary

Introduction

Toll-like receptors (TLRs) are a family of single transmembrane receptors that recognize molecular patterns from microbes or viruses and activate the innate immune system (Fig. 1a). TLRs typically exist as monomers, and ligand binding causes homodimerization or heterodimerization, transducing extracellular signals to the inside of the cell and inducing the production of inflammatory cytokines or interferons (Kawai & Akira, 2010). The LRR domains play a role in ligand recognition, and the TIR domains mediate downstream signals, accompanied by adaptor proteins that contain TIR domains, such as MyD88, TIRF, TIRAP/MAL, TRAM or SARM (Kawai & Akira, 2010). We summarize recent structural studies and discuss the mechanism by which ligand binding influences or regulates the activity of TLR8

General features of TLR8
Agonist-induced activated forms of TLR8
Inactivated forms of TLR8 stabilized by antagonists
Detailed comparison of the activated and the inactivated forms
TLR8 as a therapeutic target
Concluding remarks
Funding information

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