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 (m7G) 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 forcap N1-2'O-methylation in RIG-I tolerance of self-RNA.
CITATION STYLE
Schuberth-Wagner, C., Ludwig, J., Bruder, A. K., Herzner, A. M., Zillinger, T., Goldeck, M., … Schlee, M. (2015). A Conserved Histidine in the RNA Sensor RIG-I Controls Immune Tolerance to N1-2’O-Methylated Self RNA. Immunity, 43(1), 41–51. https://doi.org/10.1016/j.immuni.2015.06.015
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