RNA and Imidazoquinolines Are Sensed by Distinct TLR7/8 Ectodomain Sites Resulting in Functionally Disparate Signaling Events
Year: 2014
Type: article
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 loss-of-function 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.
Source: The Journal of Immunology
Authors: 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, Bénédicte Manoury, Bruce Beutler, Dominik Hartl, Alison Simmons, Alexander N R Weber
Institutions: German Cancer Research Center, University of Oxford, MRC Weatherall Institute of Molecular Medicine, University of Tübingen, Scripps Research Institute, Centre for Human Genetics, Inserm, Sorbonne Paris Cité, Université Paris Descartes, The University of Texas Southwestern Medical Center
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: Systems Approach to Immunity and Inflammation, G1535919388, The function of NOD2 in health and in Crohn's disease., Re-define Crohn’s at a molecular level to identify new biomarkers and therapies, Cellular immunology and human genetics of malaria and tuberculosis., Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G8343853698, The function of NOD2 in health and in Crohn's disease.
OpenAlex ID: W2143934902