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

Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):582-7. doi: 10.1073/pnas.0606699104. Epub 2006 Dec 26.

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-kappaB-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / metabolism
  • Cell Line
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / chemistry*
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / immunology*
  • Hepacivirus / immunology
  • Humans
  • Immunity, Innate*
  • Interferon-Induced Helicase, IFIH1
  • Models, Immunological
  • Protein Structure, Tertiary
  • RNA Helicases / chemistry*
  • RNA Helicases / genetics
  • RNA Helicases / immunology*
  • RNA, Viral / metabolism
  • Receptors, Immunologic
  • Signal Transduction

Substances

  • Antiviral Agents
  • RNA, Viral
  • Receptors, Immunologic
  • RIGI protein, human
  • IFIH1 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1
  • RNA Helicases