Regulation of innate antiviral defenses through a shared repressor domain in RIG-1 and LGP2

Takeshi Saito, Reiko Hirai, Yueh Ming Loo, David Owen, Cynthia L. Johnson, Sangita C. Sinha, Shizuo Akira, Takashi Fujita, Michael Gale

Research output: Contribution to journalArticle

501 Scopus citations

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-α/β 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 MDAS protein, demonstrated that RIG-I, but not MDAS, efficiently binds to secondary structured HCV RNA to confer induction of IFN-β 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-κB-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-β 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.

Original languageEnglish (US)
Pages (from-to)582-587
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number2
DOIs
StatePublished - Jan 9 2007

Keywords

  • Cardif
  • Hepatitis C virus
  • IFN
  • IPS-1
  • MAVS

ASJC Scopus subject areas

  • General

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