Identification of an optimized 2′-O-methylated trinucleotide RNA motif inhibiting Toll-like receptors 7 and 8

• Verfasst von: Schmitt, Felix [VerfasserIn]
• Verfasst von: Freund, Isabel [VerfasserIn]
• Verfasst von: Weigand, Markus A. [VerfasserIn]
• Verfasst von: Dalpke, Alexander [VerfasserIn]
• Verfasst von: Eigenbrod, Tatjana [VerfasserIn]
• Titel: Identification of an optimized 2′-O-methylated trinucleotide RNA motif inhibiting Toll-like receptors 7 and 8
• Verf.angabe: Felix C.F. Schmitt, Isabel Freund, Markus A. Weigand, Mark Helm, Alexander H. Dalpke, and Tatjana Eigenbrod
• Jahr: 2017
• Umfang: 8 S.
• Fussnoten: Published in advance June 2, 2017 ; Gesehen am 11.06.2018
• Titel Quelle: Enthalten in: RNA
• Ort Quelle: Cold Spring Harbor, NY : Laboratory Press, 1995
• Jahr Quelle: 2017
• Band/Heft Quelle: 23(2017), 9, Seite 1344-1351
• ISSN Quelle: 1469-9001
• DOI: doi:10.1261/rna.061952.117
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1576215601

Abstract

Bacterial RNA serves an important function as activator of the innate immune system. In humans bacterial RNA is sensed by the endosomal receptors TLR7 and TLR8. Differences in the posttranscriptional modification profile of prokaryotic when compared with eukaryotic RNA allow innate immune cells to discriminate between “host” and “foreign” RNA. Ribose 2′-O-methylation is of particular importance and has been reported to antagonize TLR7/8 activation. Yet, the exact sequence context in which 2′-O-methylation has to occur to mediate its inhibitory activity remains largely undefined. On the basis of a naturally occurring 2′-O-methylated RNA sequence, we performed a systematic permutation of the methylated nucleotide as well as adjacent bases and hereby identify two minimal trinucleotide motifs within a 9-mer oligoribonucleotide that are necessary and sufficient to antagonize TLR7 and TLR8 activation, respectively. Given the growing interest in the development of inhibitors of nucleic acid-sensing TLRs for therapeutic purposes, these results will facilitate the rational design of such antagonists in the future.