Double methylation of tRNA-U54 to 2-O-methylthymidine (Tm) synergistically decreases immune response by Toll-like receptor 7

Patrick Keller, Isabel Freund, Virginie Marchand, Guillaume Bec, Raven Huang, Yuri Motorin, Tatjana Eigenbrod, Alexander Dalpke, Mark Helm

Research output: Contribution to journalArticlepeer-review

Abstract

Sensing of nucleic acids for molecular discrimination between self and non-self is a challenging task for the innate immune system. RNA acts as a potent stimulus for pattern recognition receptors including in particular human Toll-like receptor 7 (TLR7). Certain RNA modifications limit potentially harmful self-recognition of endogenous RNA. Previous studies had identified the 2-O-methylation of guanosine 18 (Gm18) within tRNAs as an antagonist of TLR7 leading to an impaired immune response. However, human tRNALys3 was non-stimulatory despite lacking Gm18. To identify the underlying molecular principle, interferon responses of human peripheral blood mononuclear cells to differentially modified tRNALys3 were determined. The investigation of synthetic modivariants allowed attributing a significant part of the immunosilencing effect to the 2-O-methylthymidine (m5Um) modification at position 54. The effect was contingent upon the synergistic presence of both methyl groups at positions C5 and 2’O, as shown by the fact that neither Um54 nor m5U54 produced any effect alone. Testing permutations of the nucleobase at ribose-methylated position 54 suggested that the extent of silencing and antagonism of the TLR7 response was governed by hydrogen patterns and lipophilic interactions of the nucleobase. The results identify a new immune-modulatory endogenous RNA modification that limits TLR7 activation by RNA.

Original languageEnglish (US)
Pages (from-to)9764-9775
Number of pages12
JournalNucleic acids research
Volume46
Issue number18
DOIs
StatePublished - Oct 12 2018

ASJC Scopus subject areas

  • Genetics

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