A single naturally occurring 2'-O-methylation converts a TLR7- and TLR8-activating RNA into a TLR8-specific ligand

PloS One
Stephanie JungStefan Bauer

Abstract

TLR7 and TLR8 recognize RNA from pathogens and lead to subsequent immune stimulation. Here we demonstrate that a single naturally occurring 2'-O-methylation within a synthetic 18s rRNA derived RNA sequence prevents IFN-α production, however secretion of proinflammatory cytokines such as IL-6 is not impaired. By analysing TLR-deficient plasmacytoid dendritic cells and performing HEK293 genetic complementation assays we could demonstrate that the single 2'-O-methylation containing RNA still activated TLR8 but not TLR7. Therefore this specific 2'-O-ribose methylation in rRNA converts a TLR7/TLR8 ligand to an exclusively TLR8-specific ligand. Interestingly, other modifications at this position such as 2'-O-deoxy or 2'-fluoro had no strong modulating effect on TLR7 or TLR8 activation suggesting an important role of 2'-O-methylation for shaping differential TLR7 or TLR8 activation.

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Citations

Feb 1, 2019·Genes·Isabel FreundAlexander H Dalpke
Jun 2, 2018·Journal of Immunology Research·Elias A SaidDaniel Lamarre
Jan 24, 2021·Seminars in Cancer Biology·Mohammad Imran KhanHasan Mukhtar
Oct 15, 2020·Expert Opinion on Therapeutic Patents·Madeleine E KiefferW Michael Seganish
May 4, 2021·Frontiers in Molecular Biosciences·Natalia MarkelovaOlga Ozoline

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