RNA and imidazoquinolines are sensed by distinct TLR7/8 ectodomain sites resulting in functionally disparate signaling events

Elif Colak, Alasdair Leslie, Kieran Zausmer, Elham Khatamzas, Andriy V. Kubarenko, Tica Pichulik, Sascha N. Klimosch, Alice Mayer, Owen Siggs, Andreas Hector, Roman Fischer, Benedikt Klesser, Anna Rautanen, Martin Frank, Adrian V S Hill, Bélnéldicte Manoury, Bruce Beutler, Dominik Hartl, Alison Simmons, Alexander N R Weber

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

TLRs 7 and 8 are pattern recognition receptors controlling antiviral host defense or autoimmune diseases. Apart from foreign and host RNA, synthetic RNA oligoribonucleotides (ORN) or small molecules of the imidazoquinoline family activate TLR7 and 8 and are being developed as therapeutic agonists. The structure-function relationships for RNA ORN and imidazoquinoline sensing and consequent downstream signaling by human TLR7 and TLR8 are unknown. Proteome- and genome-wide analyses in primary human monocyte-derived dendritic cells here showed that TLR8 sensing of RNA ORN versus imidazoquinoline translates to ligand-specific differential phosphorylation and transcriptional events. In addition, TLR7 and 8 ectodomains were found to discriminate between RNA ORN and imidazoquinolines by overlapping and nonoverlapping recognition sites to which murine lossoffunction mutations and human naturally occurring hyporesponsive polymorphisms map. Our data suggest TLR7 and TLR8 can signal in two different "modes" depending on the class of ligand. Considering RNA ORN and imidazoquinolines have been regarded as functionally interchangeable, our study highlights important functional incongruities whose understanding will be important for developing TLR7 or 8 therapeutics with desirable effector and safety profiles for in vivo application.

Original languageEnglish (US)
Pages (from-to)5963-5973
Number of pages11
JournalJournal of Immunology
Volume192
Issue number12
DOIs
StatePublished - Jun 15 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Colak, E., Leslie, A., Zausmer, K., Khatamzas, E., Kubarenko, A. V., Pichulik, T., Klimosch, S. N., Mayer, A., Siggs, O., Hector, A., Fischer, R., Klesser, B., Rautanen, A., Frank, M., Hill, A. V. S., Manoury, B., Beutler, B., Hartl, D., Simmons, A., & Weber, A. N. R. (2014). RNA and imidazoquinolines are sensed by distinct TLR7/8 ectodomain sites resulting in functionally disparate signaling events. Journal of Immunology, 192(12), 5963-5973. https://doi.org/10.4049/jimmunol.1303058