Identification of modifications in microbial, native tRNA that suppress immunostimulatory activity
| Autor: | Florian Eberle, Volker A. Erdmann, Alexander H. Dalpke, Walter M. Holmes, Gérard Keith, Steffen Kaiser, Mathias Sprinzl, Guillaume Bec, Tatjana Eigenbrod, Mariel-Esther Eberle, Flavia Botschen, Mark Helm, Katharina Rimbach, Stefanie Gehrig |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Immunology
Mutant fungi Brief Definitive Report RNA food and beverages virus diseases Context (language use) Biology biochemical phenomena metabolism and nutrition medicine.disease_cause TRNA Methyltransferases Transplantation chemistry.chemical_compound Biochemistry chemistry Transfer RNA medicine Immunology and Allergy Escherichia coli DNA |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | 2′-O-methylation of guanosine 18 is a naturally occurring tRNA modification that can suppress immune TLR7 responses. Naturally occurring nucleotide modifications within RNA have been proposed to be structural determinants for innate immune recognition. We tested this hypothesis in the context of native nonself-RNAs. Isolated, fully modified native bacterial transfer RNAs (tRNAs) induced significant secretion of IFN-α from human peripheral blood mononuclear cells in a manner dependent on TLR7 and plasmacytoid dendritic cells. As a notable exception, tRNATyr from Escherichia coli was not immunostimulatory, as were all tested eukaryotic tRNAs. However, the unmodified, 5′-unphosphorylated in vitro transcript of tRNATyr induced IFN-α, thus revealing posttranscriptional modifications as a factor suppressing immunostimulation. Using a molecular surgery approach based on catalytic DNA, a panel of tRNATyr variants featuring differential modification patterns was examined. Out of seven modifications present in this tRNA, 2′-O-methylated Gm18 was identified as necessary and sufficient to suppress immunostimulation. Transplantation of this modification into the scaffold of yeast tRNAPhe also resulted in blocked immunostimulation. Moreover, an RNA preparation of an E. coli trmH mutant that lacks Gm18 2′-O-methyltransferase activity was significantly more stimulatory than the wild-type sample. The experiments identify the single methyl group on the 2′-oxygen of Gm18 as a natural modification in native tRNA that, beyond its primary structural role, has acquired a secondary function as an antagonist of TLR7. |
| Databáze: | OpenAIRE |
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