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Basic Characteristics of Mutations
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Mutation Site
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E218A |
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Mutation Site Sentence
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the NS5-E218A mutation impaired virus production in A549 cells to a much higher extent (>60-fold reduction, Figure 4C) than in Vero cells (<5-fold reduction, Figure 4D). |
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Mutation Level
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Amino acid level |
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Mutation Type
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Nonsynonymous substitution |
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Gene/Protein/Region
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NS5 |
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Standardized Encoding Gene
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NS5
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Genotype/Subtype
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- |
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Viral Reference
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-
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Functional Impact and Mechanisms
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Disease
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Cell line
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Immune
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- |
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Target Gene
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RIGI
STAT1
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Clinical and Epidemiological Correlations
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Clinical Information
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- |
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Treatment
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- |
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Location
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- |
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Literature Information
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PMID
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26187414
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Title
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A Conserved Histidine in the RNA Sensor RIG-I Controls Immune Tolerance to N1-2'O-Methylated Self RNA
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Author
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Schuberth-Wagner C,Ludwig J,Bruder AK,Herzner AM,Zillinger T,Goldeck M,Schmidt T,Schmid-Burgk JL,Kerber R,Wolter S,Stumpel JP,Roth A,Bartok E,Drosten C,Coch C,Hornung V,Barchet W,Kummerer BM,Hartmann G,Schlee M
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Journal
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Immunity
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Journal Info
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2015 Jul 21;43(1):41-51
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Abstract
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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 (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.
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Sequence Data
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-
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