title: The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I.
abstract: The paramyxovirus Sendai (SV), is a well-established inducer of IFN-alphabeta gene expression. In this study we show that SV induces IFN-alphabeta gene expression normally in cells from mice with targeted deletions of the Toll-IL-1 resistance domain containing adapters MyD88, Mal, Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF), and TRIF-related adaptor molecule TLR3, or the E3 ubiquitin ligase, TNFR-associated factor 6. This TLR-independent induction of IFN-alphabeta after SV infection is replication dependent and mediated by the RNA helicase, retinoic acid-inducible gene-I (RIG-I) and not the related family member, melanoma differentiation-associated gene 5. Furthermore, we characterize a RIG-I-like RNA helicase, Lgp2. In contrast to RIG-I or melanoma differentiation-associated gene 5, Lgp2 lacks signaling caspase recruitment and activation domains. Overexpression of Lgp2 inhibits SV and Newcastle disease virus signaling to IFN-stimulated regulatory element- and NF-kappaB-dependent pathways. Importantly, Lgp2 does not prevent TLR3 signaling. Like RIG-I, Lgp2 binds double-stranded, but not single-stranded, RNA. Quantitative PCR analysis demonstrates that Lgp2 is present in unstimulated cells at a lower level than RIG-I, although both helicases are induced to similar levels after virus infection. We propose that Lgp2 acts as a negative feedback regulator of antiviral signaling by sequestering dsRNA from RIG-I.
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Rothenfusser
authors.forename: Nadege
authors.initials: N
authors.lastname: Goutagny
authors.forename: Gary
authors.initials: G
authors.lastname: DiPerna
authors.forename: Mei
authors.initials: M
authors.lastname: Gong
authors.forename: Brian G
authors.initials: BG
authors.lastname: Monks
authors.forename: Annett
authors.initials: A
authors.lastname: Schoenemeyer
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics; D002460:Cell Line; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000235:genetics; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88; D011510:Proteolipids / Q000235:genetics; D020365:RNA Helicases / Q000502:physiology*; D012330:RNA, Double-Stranded / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics; D029082:Sendai virus / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000943:Antigens, Differentiation; D026901:Membrane Transport Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88; D011510:Proteolipids; D020365:RNA Helicases; D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; D048029:TNF Receptor-Associated Factor 6; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D015534:Trans-Activators; C569026:MAL protein, human; C507779:MYD88 protein, human; C569027:Mal protein, mouse; C507780:Myd88 protein, mouse; C502844:Rai1 protein, mouse; C476286:Ticam1 protein, mouse; C520569:DHX58 protein, human