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

Publication type:
Journal article
Metadata:
Autoren
  • Patrick Keller
  • Isabel Freund
  • Virginie Marchand
  • Guillaume Bec
  • Raven Huang
  • Yuri Motorin
  • Tatjana Eigenbrod
  • Alexander Dalpke
  • Mark Helm
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000450953200046&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1093/nar/gky644
eISSN
1362-4962
Externe Identifier
  • Clarivate Analytics Document Solution ID: HB3LO
  • PubMed Identifier: 30102387
ISSN
0305-1048
Ausgabe der Veröffentlichung
18
Zeitschrift
NUCLEIC ACIDS RESEARCH
Paginierung
9764 - 9775
Datum der Veröffentlichung
2018
Status
Published
Titel
Double methylation of tRNA-U54 to 2′-O-methylthymidine (Tm) synergistically decreases immune response by Toll-like receptor 7
Sub types
  • Article
Ausgabe der Zeitschrift
46

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Patrick Keller
  • Isabel Freund
  • Virginie Marchand
  • Guillaume Bec
  • Raven Huang
  • Yuri Motorin
  • Tatjana Eigenbrod
  • Alexander Dalpke
  • Mark Helm
DOI
10.1093/nar/gky644
eISSN
1362-4962
ISSN
0305-1048
Ausgabe der Veröffentlichung
18
Zeitschrift
Nucleic Acids Research
Sprache
en
Online publication date
2018
Paginierung
9764 - 9775
Datum der Veröffentlichung
2018
Status
Published
Herausgeber
Oxford University Press (OUP)
Herausgeber URL
http://dx.doi.org/10.1093/nar/gky644
Datum der Datenerfassung
2022
Titel
Double methylation of tRNA-U54 to 2′-O-methylthymidine (Tm) synergistically decreases immune response by Toll-like receptor 7
Ausgabe der Zeitschrift
46

Data source: Crossref

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.
Addresses
  • Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University of Mainz, Staudingerweg 5, D-55128 Mainz, Germany.
Autoren
  • Patrick Keller
  • Isabel Freund
  • Virginie Marchand
  • Guillaume Bec
  • Raven Huang
  • Yuri Motorin
  • Tatjana Eigenbrod
  • Alexander Dalpke
  • Mark Helm
DOI
10.1093/nar/gky644
eISSN
1362-4962
Externe Identifier
  • PubMed Identifier: 30102387
  • PubMed Central ID: PMC6182150
Funding acknowledgements
  • DFG: HE 3397/13-1 (SPP1784)
  • ANR-DFG Joint: ANR-13-ISV8-0001/HE 3397/8-1
  • DFG: DA 592/5-1
  • DFG: HE 3397/9-1
Open access
true
ISSN
0305-1048
Ausgabe der Veröffentlichung
18
Zeitschrift
Nucleic acids research
Schlüsselwörter
  • Leukocytes, Mononuclear
  • Humans
  • Hydrogen
  • Interferons
  • Nucleic Acids
  • RNA, Transfer
  • Thymidine
  • Guanosine
  • Methylation
  • Toll-Like Receptor 7
  • Immunity, Innate
Sprache
eng
Medium
Print
Open access status
Open Access
Paginierung
9764 - 9775
Datum der Veröffentlichung
2018
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2018
Titel
Double methylation of tRNA-U54 to 2'-O-methylthymidine (Tm) synergistically decreases immune response by Toll-like receptor 7.
Sub types
  • Research Support, Non-U.S. Gov't
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
46

Files

https://academic.oup.com/nar/article-pdf/46/18/9764/26001760/gky644.pdf https://europepmc.org/articles/PMC6182150?pdf=render

Data source: Europe PubMed Central

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.
Date of acceptance
2018
Autoren
  • Patrick Keller
  • Isabel Freund
  • Virginie Marchand
  • Guillaume Bec
  • Raven Huang
  • Yuri Motorin
  • Tatjana Eigenbrod
  • Alexander Dalpke
  • Mark Helm
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/30102387
DOI
10.1093/nar/gky644
eISSN
1362-4962
Externe Identifier
  • PubMed Central ID: PMC6182150
Ausgabe der Veröffentlichung
18
Zeitschrift
Nucleic Acids Res
Schlüsselwörter
  • Guanosine
  • Humans
  • Hydrogen
  • Immunity, Innate
  • Interferons
  • Leukocytes, Mononuclear
  • Methylation
  • Nucleic Acids
  • RNA, Transfer
  • Thymidine
  • Toll-Like Receptor 7
Sprache
eng
Country
England
Paginierung
9764 - 9775
PII
5068253
Datum der Veröffentlichung
2018
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2019
Titel
Double methylation of tRNA-U54 to 2'-O-methylthymidine (Tm) synergistically decreases immune response by Toll-like receptor 7.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
46

Data source: PubMed

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