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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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