Reports

Cytosolic Viral Sensor RIG-I Is a 5'-Triphosphate–Dependent Translocase on Double-Stranded RNA

Sua Myong,^1* Sheng Cui,^2* Peter V. Cornish,^3,4 Axel Kirchhofer,² Michaela U. Gack,^5,6,7 Jae U. Jung,^5,6 Karl-Peter Hopfner,² Taekjip Ha^1,3,4

Retinoic acid inducible–gene I (RIG-I) is a cytosolic multidomain protein that detects viral RNA and elicits an antiviral immune response. Two N-terminal caspase activation and recruitment domains (CARDs) transmit the signal, and the regulatory domain prevents signaling in the absence of viral RNA. 5'-triphosphate and double-stranded RNA (dsRNA) are two molecular patterns that enable RIG-I to discriminate pathogenic from self-RNA. However, the function of the DExH box helicase domain that is also required for activity is less clear. Using single-molecule protein-induced fluorescence enhancement, we discovered a robust adenosine 5'-triphosphate–powered dsRNA translocation activity of RIG-I. The CARDs dramatically suppress translocation in the absence of 5'-triphosphate, and the activation by 5'-triphosphate triggers RIG-I to translocate preferentially on dsRNA in cis. This functional integration of two RNA molecular patterns may provide a means to specifically sense and counteract replicating viruses.

¹ Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Champaign, IL 61801, USA.
² Center for Integrated Protein Science and Munich Center for Advanced Photonics at the Gene Center, Ludwig-Maximilians-University of Munich, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.
³ Department of Physics and Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Room 133, Loomis Laboratory, MC 704, 1110 West Green Street, Urbana, IL 61801, USA.
⁴ Howard Hughes Medical Institute, Urbana, IL, USA.
⁵ Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Harlyne J. Norris Cancer Research Tower, 1450 Biggy Street, Los Angeles, CA 90033, USA.
⁶ Department of Microbiology and Molecular Genetics and Tumor Virology Division, New England Primate Research Center, Harvard Medical School, 1 Pine Hill Drive, Southborough, MA 01772, USA.
⁷ Institute for Clinical and Molecular Virology, Friedrich-Alexander-University Erlangen-Nuremberg, Schlossgarten 4, 91054 Erlangen, Germany.

^* These authors contributed equally to this work.

To whom correspondence should be addressed. E-mail: smyong{at}uiuc.edu (S.M.); hopfner{at}lmb.uni-muenchen.de (K.-P.H.); tjha{at}uiuc.edu (T.H.)

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V. D. Menachery and D. A. Leib (2009)
J. Virol. 83, 12399-12406
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X. Xiao, P. Zhao, D. Rodriguez-Pinto, D. Qi, O. Henegariu, L. Alexopoulou, R. A. Flavell, F. S. Wong, and L. Wen (2009)
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5'-triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I.

A. Schmidt, T. Schwerd, W. Hamm, J. C. Hellmuth, S. Cui, M. Wenzel, F. S. Hoffmann, M.-C. Michallet, R. Besch, K.-P. Hopfner, et al. (2009)
PNAS 106, 12067-12072
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