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PNAS 104 (2): 582-587

Copyright © 2007 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / IMMUNOLOGY

Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2

Takeshi Saito*, Reiko Hirai{dagger}, Yueh-Ming Loo*, David Owen*, Cynthia L. Johnson*, Sangita C. Sinha{ddagger}, Shizuo Akira§, Takashi Fujita{dagger}, and Michael Gale, Jr.*

Departments of *Microbiology and {ddagger}Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas, TX 75235-9048; {dagger}Department of Genetics and Molecular Biology, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; and §Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 560-0043, Japan

Edited by Peter Palese, Mount Sinai School of Medicine, New York, NY, and approved November 1, 2006

Received for publication August 3, 2006.

Abstract: RIG-I is an RNA helicase containing caspase activation and recruitment domains (CARDs). RNA binding and signaling by RIG-I are implicated in pathogen recognition and triggering of IFN-{alpha}/beta immune defenses that impact cell permissiveness for hepatitis C virus (HCV). Here we evaluated the processes that control RIG-I signaling. RNA binding studies and analysis of cells lacking RIG-I, or the related MDA5 protein, demonstrated that RIG-I, but not MDA5, efficiently binds to secondary structured HCV RNA to confer induction of IFN-beta expression. We also found that LGP2, a helicase related to RIG-I and MDA5 but lacking CARDs and functioning as a negative regulator of host defense, binds HCV RNA. In resting cells, RIG-I is maintained as a monomer in an autoinhibited state, but during virus infection and RNA binding it undergoes a conformation shift that promotes self-association and CARD interactions with the IPS-1 adaptor protein to signal IFN regulatory factor 3- and NF-{kappa}B-responsive genes. This reaction is governed by an internal repressor domain (RD) that controls RIG-I multimerization and IPS-1 interaction. Deletion of the RIG-I RD resulted in constitutive signaling to the IFN-beta promoter, whereas RD expression alone prevented signaling and increased cellular permissiveness to HCV. We identified an analogous RD within LGP2 that interacts in trans with RIG-I to ablate self-association and signaling. Thus, RIG-I is a cytoplasmic sensor of HCV and is governed by RD interactions that are shared with LGP2 as an on/off switch controlling innate defenses. Modulation of RIG-I/LGP2 interaction dynamics may have therapeutic implications for immune regulation.

Key Words: hepatitis C virus • IFN • IPS-1 • MAVS • Cardif


Author contributions: T.S., R.H., C.L.J., T.F., and M.G. designed research; T.S., R.H., Y.-M.L., D.O., C.L.J., S.C.S., T.F., and M.G. performed research; T.S., Y.-M.L., S.A., and M.G. contributed new reagents/analytic tools; T.S., D.O., C.L.J., S.C.S., T.F., and M.G. analyzed data; and T.S. and R.H. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS direct submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0606699104/DC1.

To whom correspondence should be addressed at: Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9048. E-mail: michael.gale{at}utsouthwestern.edu

© 2007 by The National Academy of Sciences of the USA


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Y.-M. Loo, J. Fornek, N. Crochet, G. Bajwa, O. Perwitasari, L. Martinez-Sobrido, S. Akira, M. A. Gill, A. Garcia-Sastre, M. G. Katze, et al. (2008)
J. Virol. 82, 335-345
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Hepatitis C virus non-structural proteins responsible for suppression of the RIG-I/Cardif-induced interferon response.
M. Tasaka, N. Sakamoto, Y. Itakura, M. Nakagawa, Y. Itsui, Y. Sekine-Osajima, Y. Nishimura-Sakurai, C.-H. Chen, M. Yoneyama, T. Fujita, et al. (2007)
J. Gen. Virol. 88, 3323-3333
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Hepatitis C Virus Infection Induces the Beta Interferon Signaling Pathway in Immortalized Human Hepatocytes.
T. Kanda, R. Steele, R. Ray, and R. B. Ray (2007)
J. Virol. 81, 12375-12381
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IFN-{varepsilon} Mediates TNF-{alpha}-Induced STAT1 Phosphorylation and Induction of Retinoic Acid-Inducible Gene-I in Human Cervical Cancer Cells.
T. Matsumiya, S. M. Prescott, and D. M. Stafforini (2007)
J. Immunol. 179, 4542-4549
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Triggering the Innate Antiviral Response through IRF-3 Activation.
J. Hiscott (2007)
J. Biol. Chem. 282, 15325-15329
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Function of RIG-I-like Receptors in Antiviral Innate Immunity.
M. Yoneyama and T. Fujita (2007)
J. Biol. Chem. 282, 15315-15318
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Loss of DExD/H Box RNA Helicase LGP2 Manifests Disparate Antiviral Responses.
T. Venkataraman, M. Valdes, R. Elsby, S. Kakuta, G. Caceres, S. Saijo, Y. Iwakura, and G. N. Barber (2007)
J. Immunol. 178, 6444-6455
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Regulation of Interferon Production by RIG-I and LGP2: A Lesson in Self-Control.
D. Vitour and E. F. Meurs (2007)
Sci. STKE 2007, pe20
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Functional and Therapeutic Analysis of Hepatitis C Virus NS3{middle dot}4A Protease Control of Antiviral Immune Defense.
C. L. Johnson, D. M. Owen, and M. Gale Jr. (2007)
J. Biol. Chem. 282, 10792-10803
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