title: Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2.
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.
authors.affiliation: Department of Microbiology, Division of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas, TX 75235-9048, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Saito
authors.forename: Reiko
authors.initials: R
authors.lastname: Hirai
authors.forename: Yueh-Ming
authors.initials: YM
authors.lastname: Loo
authors.forename: David
authors.initials: D
authors.lastname: Owen
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Johnson
authors.forename: Sangita C
authors.initials: SC
authors.lastname: Sinha
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujita
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D016174:Hepacivirus / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D000072640:Interferon-Induced Helicase, IFIH1; D018448:Models, Immunological; D017434:Protein Structure, Tertiary; D020365:RNA Helicases / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D012367:RNA, Viral / Q000378:metabolism; D011971:Receptors, Immunologic; D015398:Signal Transduction
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; D011971:Receptors, Immunologic; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D020365:RNA Helicases