Journal Article

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

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

2007

Overview

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 MDA5 protein, demonstrated that RIG-I, but not MDA5, 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Amino acids / Antiviral Agents - metabolism / Binding sites / Biological Sciences / caspases / Cell Line / Cell lines / Cellular immunity / DEAD Box Protein 58 / DEAD-box RNA Helicases - chemistry / DEAD-box RNA Helicases - genetics / DEAD-box RNA Helicases - immunology / Double stranded RNA / genes / Hepacivirus - immunology / Hepatitis / Hepatitis C virus / Humans / immune response / Immune system / Immunity, Innate / Infections / interferon-beta / Interferon-Induced Helicase, IFIH1 / Models, Immunological / pathogens / Permissiveness / Plasmids / Protein Structure, Tertiary / Proteins / Receptors, Immunologic / Ribonucleic acid / Ribozymes / RNA / RNA helicases / RNA Helicases - chemistry / RNA Helicases - genetics / RNA Helicases - immunology / RNA, Viral - metabolism / Signal Transduction / Viruses