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Science 314 (5801): 994-997

Copyright © 2006 by the American Association for the Advancement of Science

5'-Triphosphate RNA Is the Ligand for RIG-I

Veit Hornung,1 Jana Ellegast,1 Sarah Kim,1 Krzysztof Brzózka,3 Andreas Jung,2 Hiroki Kato,2 Hendrik Poeck,1 Shizuo Akira,2 Karl-Klaus Conzelmann,3 Martin Schlee,4 Stefan Endres,1 Gunther Hartmann4*

Abstract: The structural basis for the distinction of viral RNA from abundant self RNA in the cytoplasm of virally infected cells is largely unknown. We demonstrated that the 5'-triphosphate end of RNA generated by viral polymerases is responsible for retinoic acid–inducible protein I (RIG-I)–mediated detection of RNA molecules. Detection of 5'-triphosphate RNA is abrogated by capping of the 5'-triphosphate end or by nucleoside modification of RNA, both occurring during posttranscriptional RNA processing in eukaryotes. Genomic RNA prepared from a negative-strand RNA virus and RNA prepared from virus-infected cells (but not from noninfected cells) triggered a potent interferon-{alpha} response in a phosphatase-sensitive manner. 5'-triphosphate RNA directly binds to RIG-I. Thus, uncapped 5'-triphosphate RNA (now termed 3pRNA) present in viruses known to be recognized by RIG-I, but absent in viruses known to be detected by MDA-5 such as the picornaviruses, serves as the molecular signature for the detection of viral infection by RIG-I.

1 Division of Clinical Pharmacology, Department of Internal Medicine, University of Munich, 80336 Munich, Germany.
2 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita 565–0871, Osaka, Japan.
3 Department of Virology, Max von Pettenkofer Institute and Gene Center, University of Munich, 81377 Munich, Germany.
4 Division of Clinical Pharmacology, University Hospital, University of Bonn, 53105 Bonn, Germany.

* To whom correspondence should be addressed. E-mail: gunther.hartmann{at}ukb.uni-bonn.de

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Genetic Dissection of Interferon-Antagonistic Functions of Rabies Virus Phosphoprotein: Inhibition of Interferon Regulatory Factor 3 Activation Is Important for Pathogenicity.
M. Rieder, K. Brzozka, C. K. Pfaller, J. H. Cox, L. Stitz, and K.-K. Conzelmann (2011)
J. Virol. 85, 842-852
   Abstract »    Full Text »    PDF »
Chikungunya Virus Induces IPS-1-Dependent Innate Immune Activation and Protein Kinase R-Independent Translational Shutoff.
L. K. White, T. Sali, D. Alvarado, E. Gatti, P. Pierre, D. Streblow, and V. R. DeFilippis (2011)
J. Virol. 85, 606-620
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Evolutional Conservation of Molecular Structure and Antiviral Function of a Viral RNA Receptor, LGP2, in Japanese Flounder, Paralichthys olivaceus.
M. Ohtani, J.-i. Hikima, H. Kondo, I. Hirono, T.-S. Jung, and T. Aoki (2010)
J. Immunol. 185, 7507-7517
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Antagonism of Type I Interferon Responses by New World Hantaviruses.
J. R. Levine, J. Prescott, K. S. Brown, S. M. Best, H. Ebihara, and H. Feldmann (2010)
J. Virol. 84, 11790-11801
   Abstract »    Full Text »    PDF »
RNAi-mediated immunity provides strong protection against the negative-strand RNA vesicular stomatitis virus in Drosophila.
S. Mueller, V. Gausson, N. Vodovar, S. Deddouche, L. Troxler, J. Perot, S. Pfeffer, J. A. Hoffmann, M.-C. Saleh, and J.-L. Imler (2010)
PNAS 107, 19390-19395
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Early Innate Recognition of Herpes Simplex Virus in Human Primary Macrophages Is Mediated via the MDA5/MAVS-Dependent and MDA5/MAVS/RNA Polymerase III-Independent Pathways.
J. Melchjorsen, J. Rintahaka, S. Soby, K. A. Horan, A. Poltajainen, L. Ostergaard, S. R. Paludan, and S. Matikainen (2010)
J. Virol. 84, 11350-11358
   Abstract »    Full Text »    PDF »
Induction of type I interferon by adenovirus-encoded small RNAs.
T. Yamaguchi, K. Kawabata, E. Kouyama, K. J. Ishii, K. Katayama, T. Suzuki, S. Kurachi, F. Sakurai, S. Akira, and H. Mizuguchi (2010)
PNAS 107, 17286-17291
   Abstract »    Full Text »    PDF »
Inhibition of Hepatitis C Virus Replication by IFN-Mediated ISGylation of HCV-NS5A.
M.-J. Kim and J.-Y. Yoo (2010)
J. Immunol. 185, 4311-4318
   Abstract »    Full Text »    PDF »
Preference of RIG-I for short viral RNA molecules in infected cells revealed by next-generation sequencing.
A. Baum, R. Sachidanandam, and A. Garcia-Sastre (2010)
PNAS 107, 16303-16308
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Activation of the Interferon Response by Human Cytomegalovirus Occurs via Cytoplasmic Double-Stranded DNA but Not Glycoprotein B.
V. R. DeFilippis, T. Sali, D. Alvarado, L. White, W. Bresnahan, and K. J. Fruh (2010)
J. Virol. 84, 8913-8925
   Abstract »    Full Text »    PDF »
Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation.
B. R. Anderson, H. Muramatsu, S. R. Nallagatla, P. C. Bevilacqua, L. H. Sansing, D. Weissman, and K. Kariko (2010)
Nucleic Acids Res. 38, 5884-5892
   Abstract »    Full Text »    PDF »
The 3C Protein of Enterovirus 71 Inhibits Retinoid Acid-Inducible Gene I-Mediated Interferon Regulatory Factor 3 Activation and Type I Interferon Responses.
X. Lei, X. Liu, Y. Ma, Z. Sun, Y. Yang, Q. Jin, B. He, and J. Wang (2010)
J. Virol. 84, 8051-8061
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TLR3 and Rig-Like Receptor on Myeloid Dendritic Cells and Rig-Like Receptor on Human NK Cells Are Both Mandatory for Production of IFN-{gamma} in Response to Double-Stranded RNA.
I. Perrot, F. Deauvieau, C. Massacrier, N. Hughes, P. Garrone, I. Durand, O. Demaria, N. Viaud, L. Gauthier, M. Blery, et al. (2010)
J. Immunol. 185, 2080-2088
   Abstract »    Full Text »    PDF »
Double-stranded RNA-dependent ATPase DRH-3: INSIGHT INTO ITS ROLE IN RNA SILENCING IN CAENORHABDITIS ELEGANS.
C. Matranga and A. M. Pyle (2010)
J. Biol. Chem. 285, 25363-25371
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