1. A Conserved Histidine in the RNA Sensor RIG-I Controls Immune Tolerance to N1-2′O-Methylated Self RNA.
- Author
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Schuberth-Wagner, Christine, Ludwig, Janos, Bruder, Ann Kristin, Herzner, Anna-Maria, Zillinger, Thomas, Goldeck, Marion, Schmidt, Tobias, Schmid-Burgk, Jonathan L., Kerber, Romy, Wolter, Steven, Stümpel, Jan-Philip, Roth, Andreas, Bartok, Eva, Drosten, Christian, Coch, Christoph, Hornung, Veit, Barchet, Winfried, Kümmerer, Beate M., Hartmann, Gunther, and Schlee, Martin
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RNA viruses , *HISTIDINE , *PHYSIOLOGICAL effects of tretinoin , *MESSENGER RNA , *IMMUNOLOGICAL tolerance , *RNA methylation - Abstract
Summary 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. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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