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Immunity. 2015 Jul 21;43(1):41-51. doi: 10.1016/j.immuni.2015.06.015. Epub 2015 Jul 14.

A Conserved Histidine in the RNA Sensor RIG-I Controls Immune Tolerance to N1-2'O-Methylated Self RNA.

Author information

1
Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53105 Bonn, Germany.
2
Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53105 Bonn, Germany; German Center for Infection Research Cologne-Bonn.
3
Institute of Molecular Medicine, University Hospital, University of Bonn, 53105 Bonn, Germany.
4
Department of Virology, Bernhard-Nocht-Institute for Tropical Medicine, 20259 Hamburg, Germany.
5
Institute of Virology, University of Bonn Medical Centre, 53127 Bonn, Germany.
6
Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53105 Bonn, Germany. Electronic address: martin.schlee@uni-bonn.de.

Abstract

The cytosolic helicase retinoic acid-inducible gene-I (RIG-I) initiates immune responses to most RNA viruses by detecting viral 5'-triphosphorylated RNA (pppRNA). Although endogenous mRNA is also 5'-triphosphorylated, backbone modifications and the 5'-ppp-linked methylguanosine ((m7)G) cap prevent immunorecognition. Here we show that the methylation status of endogenous capped mRNA at the 5'-terminal nucleotide (N1) was crucial to prevent RIG-I activation. Moreover, we identified a single conserved amino acid (H830) in the RIG-I RNA binding pocket as the mediator of steric exclusion of N1-2'O-methylated RNA. H830A alteration (RIG-I(H830A)) restored binding of N1-2'O-methylated pppRNA. Consequently, endogenous mRNA activated the RIG-I(H830A) mutant but not wild-type RIG-I. Similarly, knockdown of the endogenous N1-2'O-methyltransferase led to considerable RIG-I stimulation in the absence of exogenous stimuli. Studies involving yellow-fever-virus-encoded 2'O-methyltransferase and RIG-I(H830A) revealed that viruses exploit this mechanism to escape RIG-I. Our data reveal a new role for cap N1-2'O-methylation in RIG-I tolerance of self-RNA.

KEYWORDS:

2′O-methyl; 5′-triphosphate RNA; MTr1; RIG-I; cap; immune recognition of RNA; innate immune tolerance mechanism; mRNA; virus

PMID:
26187414
DOI:
10.1016/j.immuni.2015.06.015
[Indexed for MEDLINE]
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