Journal
IMMUNITY
Volume 43, Issue 1, Pages 41-51Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2015.06.015
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Funding
- Deutsche Forschungsgemeinschaft [SFB670, DFG SCHL1930/1-1, SFB704, SFB832, KFO177, KU1201/4-1]
- University Hospital of Bonn (BONFOR)
- DFG Excellence Cluster ImmunoSensation
- German Center of Infectious Disease (DZIF)
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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 (N-1) 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 N-1-2'O-methylated RNA. H830A alteration (RIG-I(H830A)) restored binding of N-1-2'O-methylated pppRNA. Consequently, endogenous mRNA activated the RIG-I(H830A) mutant but not wild-type RIG-I. Similarly, knockdown of the endogenous N-1-2'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 N-1-2'O-methylation in RIG-I tolerance of self-RNA.
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