Toll-like receptor 8 senses degradation products of single-stranded RNA
Abstract
Toll-like receptor 8 (TLR8) recognizes viral or bacterial single-stranded RNA (ssRNA) and activates innate immune systems. TLR8 is activated by uridine- and guanosine-rich ssRNA as well as by certain synthetic chemicals; however, the molecular basis for ssRNA recognition has remained unknown. In this study, to elucidate the recognition mechanism of ssRNA, we determined the crystal structures of human TLR8 in complex with ssRNA. TLR8 recognized two degradation products of ssRNA—uridine and a short oligonucleotide—at two distinct sites: uridine bound the site on the dimerization interface where small chemical ligands are recognized, whereas short oligonucleotides bound a newly identified site on the concave surface of the TLR8 horseshoe structure. Site-directed mutagenesis revealed that both binding sites were essential for activation of TLR8 by ssRNA. These results demonstrate that TLR8 is a sensor for both uridine and a short oligonucleotide derived from RNA.
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The ligands of TLR7 and TLR8 are degradation products of RNA including short stretches of ssRNA and nucleosides.
“Recently, the ligands of TLR7 and TLR8 have been reported as degradation products of RNA including short stretches of ssRNA and nucleosides (Tanji et al. 2015; Zhang et al. 2016).”
From RNA Circularization Diminishes Immunogenicity and Can Extend Translation Duration In Vivo (2019) · cites this paper as Tanji et al. 2015
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“Myeloid dendritic cells and monocytes express TLR 8 which binds to uridine and GU motifs and promotes the secretion of pro-inflammatory cytokines (30).”
Background
- Authors
- Tanji, H., Ohto, U., Shibata, T., Taoka, M., Yamauchi, Y., Isobe, T., Miyake, K., & Shimizu, T.
- Affiliations
- The University of Tokyo (JP)
- Japan Science and Technology Agency (JP)
- Tokyo Metropolitan University (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- Corresponding author
- Shimizu, Toshiyuki
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2015-01-19
- Volume
- 22
- Issue
- 2
- Pages
- 109-115
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W2147763501
- Cited by
- 404
- References
- 41
- Citations by year
- 2026: 29 · 2025: 34 · 2024: 41 · 2023: 40 · 2022: 38 · 2021: 62 · 2020: 31 · 2019: 30 · 2018: 28 · 2017: 26 · 2016: 30 · 2015: 15
- FWCI
- 16.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (26670235, 15J12485, 25253032, 25291010)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- TLR8, single-stranded RNA, uridine, innate immunity, ligand recognition
- MeSH terms
- Animals, Binding Sites, Calorimetry, Cell Line, Chromatography, Liquid, Drosophila, Humans, RNA, Mass Spectrometry, Mutagenesis, Site-Directed, Protein Structure, Tertiary, Crystallography, X-Ray, Toll-Like Receptor 8
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