Title |
A Conserved Histidine in the RNA Sensor RIG-I Controls Immune Tolerance to N1-2′O-Methylated Self RNA
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Published in |
Immunity, July 2015
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DOI | 10.1016/j.immuni.2015.06.015 |
Pubmed ID | |
Authors |
Christine Schuberth-Wagner, Janos Ludwig, Ann Kristin Bruder, Anna-Maria Herzner, Thomas Zillinger, Marion Goldeck, Tobias Schmidt, Jonathan L. Schmid-Burgk, Romy Kerber, Steven Wolter, Jan-Philip Stümpel, Andreas Roth, Eva Bartok, Christian Drosten, Christoph Coch, Veit Hornung, Winfried Barchet, Beate M. Kümmerer, Gunther Hartmann, Martin Schlee |
Abstract |
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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Geographical breakdown
Country | Count | As % |
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Chile | 1 | 20% |
United States | 1 | 20% |
Germany | 1 | 20% |
Unknown | 2 | 40% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 5 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Germany | 2 | <1% |
Japan | 1 | <1% |
United States | 1 | <1% |
Korea, Republic of | 1 | <1% |
Unknown | 271 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 68 | 25% |
Researcher | 44 | 16% |
Student > Bachelor | 33 | 12% |
Student > Master | 32 | 12% |
Student > Doctoral Student | 11 | 4% |
Other | 29 | 11% |
Unknown | 59 | 21% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 74 | 27% |
Agricultural and Biological Sciences | 63 | 23% |
Immunology and Microbiology | 33 | 12% |
Medicine and Dentistry | 19 | 7% |
Chemistry | 7 | 3% |
Other | 21 | 8% |
Unknown | 59 | 21% |