C-ter TLR7 dimer binds TLR7, TLR8 ligands

Stable Identifier
R-HSA-167983
Type
Reaction
Species
Homo sapiens
Related Species
Human immunodeficiency virus 1, Influenza A virus, Human SARS coronavirus, Severe acute respiratory syndrome coronavirus 2
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Endosomal recognition of viral single stranded (ss) RNA occurs by means of toll-like receptor 7 (TLR7) and TLR8. TLR7 and TLR8 detect GU-rich ssRNA sequences from the viral genomes of orthomyxovirus (influenza A), lentivirus (human immunodeficiency virus-1, HIV-1), vesiculovirus (vesicular stomatitis virus, VSV), enterovirus (coxsackie B virus), betacoronavirus (severe acute respiratory syndrome-associated coronavirus type 1, SARS-CoV-1 and SARS-CoV-2) and flavivirus (HCV and WNV) (Hemmi H et al. 2002; Jurk M et al. 2002; Diebold SS et al. 2004; Heil F et al. 2004; Cervantes-Barragan L et al. 2007; Li Y et al. 2013; Scheuplein VA et al. 2015; Campbell GR et al. 2021; reviewed in Lester SN & Li K 2014). Specifically, GU-rich ssRNA oligonucleotides derived from HIV-1, for example, stimulate dendritic cells (DC) and macrophages to secrete interferon-alpha and proinflammatory, as well as regulatory, cytokines (Heil F et al. 2004). This has been found to be mediated by TLR7, as well as TLR8. Similarly, ssRNA derived from SARS‑CoV‑1 induced mononuclear phagocytes to release considerable levels of pro‑inflammatory cytokines TNF‑a, IL‑6 and IL‑12 via TLR7 and TLR8 (Li Y et al. 2013). Bioinformatics scanning techniques showed that the SARS‑CoV‑2 genome contains a large number of fragments that could be recognized by TLR7/TLR8 (Moreno‑Eutimio MA et al. 2020). In human macrophages, GU-rich RNA derived from SARS-CoV-2, SARS-CoV-1, and HIV-1 triggered TLR8-mediated pro-inflammatory responses leading to activation of the NLRP3 inflammasome and IL-1β secretion (Campbell GR et al. 2021). Upon engagement of ssRNAs in endosomes, TLR7 and TLR8 initiate the MyD88‑dependent pathway, leading to production of type I and type III IFNs and proinflammatory mediators via activation of IRF7 and NF‑κB, respectively (reviewed in Lester SN & Li K 2014). In addition, imidazoquinoline compounds (e.g. imiquimod and R‑848, a small‑molecule immune response modifier that can induce the synthesis of interferon‑alpha) were reported to be ligands of TLR7 and TLR8 (Hemmi H et al. 2002; Jurk M et al. 2002; Diebold SS et al. 2004). Structural analyses have revealed that both TLR7 and TLR8 possess two binding sites (Zhang Z et al. 2016). Binding site 1 is highly conserved between TLR7 and TLR8 and binds nucleosides (guanosine (G) for TLR7 and uridine (U) for TLR8) or base analogs. Binding site 2 of TLR7 and TLR8 is less conserved and binds ssRNA with U(U) and U(G) motifs. TLR7 acts as a dual receptor for G and U‑containing ssRNAs. Binding of ssRNA to the site 2 of TLR7 strongly enhances the interaction of TLR7 and G at the first site leading to subsequent receptor dimerization. Conversely, chemical ligands are sufficiently potent to induce TLR7 dimerization by binding to the first site alone (Zhang Z et al. 2016, 2018). Further, upon ligand stimulation, the TLR8 dimer was reorganized such that the two C termini were brought into proximity (Tanji H et al. 2013). The loop between leucine‑rich repeat 14 (LRR14) and LRR15 was cleaved, but the N‑ and C‑terminal halves remained associated and contributed to ligand recognition and dimerization, which enables the downstream signaling activation of IRF and NF‑κB (Tanji H et al. 2013, 2016). Although TLR7 and TLR8 share structural homology and both sense viral GU-rich ssRNA, their binding affinities to TLR7/TLR8 ligands may differ (Li Y et al. 2013; Campbell GR et al. 2021). TLR7‑specific ligands generally induce IFN‑regulated cytokines, but TLR8‑specific ligands lead primarily to the production of proinflammatory cytokines (Gorden KB et al. 2005).

Hydroxychloroquine (HCQ) binds and antagonizes TLR7 (Lamphier M et al. 2014), and thus inhibits interferon alpha production. HCQ is used clinically to treat systemic lupus erythromatosis and other autoimmune disorders (Costedoat‑Chalumeau N et al. 2014).

Literature References
PubMed ID Title Journal Year
12032557 Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848

Bauer, S, Lipford, G, Vollmer, J, Wagner, H, Jurk, M, Krieg, AM, Heil, F, Schetter, C

Nat Immunol 2002
14976261 Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA

Reis e Sousa, C, Diebold, SS, Akira, S, Kaisho, T, Hemmi, H

Science 2004
23123977 Extraordinary GU-rich single-strand RNA identified from SARS coronavirus contributes an excessive innate immune response

Li, Y, Cao, H, Zhu, Y, Zheng, J, Chen, M, Zhou, H

Microbes Infect. 2013
11812998 Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway

Takeuchi, O, Horiuchi, T, Hoshino, K, Sanjo, H, Tomizawa, H, Sato, S, Takeda, K, Akira, S, Kaisho, T, Hemmi, H

Nat Immunol 2002
14976262 Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8

Kirschning, C, Bauer, S, Lipford, G, Hochrein, H, Akira, S, Wagner, H, Ampenberger, F, Heil, F, Hemmi, H

Science 2004
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