| First Author | Schuberth-Wagner C | Year | 2015 |
| Journal | Immunity | Volume | 43 |
| Issue | 1 | Pages | 41-51 |
| PubMed ID | 26187414 | Mgi Jnum | J:259393 |
| Mgi Id | MGI:6140284 | Doi | 10.1016/j.immuni.2015.06.015 |
| Citation | Schuberth-Wagner C, et al. (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 |
| abstractText | 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. |
