The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I
Department of Medicine, Division of Infectious Diseases and Immunology
Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Animals; Antigens, Differentiation; Cell Line; Humans; Membrane Transport Proteins; Mice; Mice, Knockout; Myelin Proteins; Myeloid Differentiation Factor 88; Proteolipids; RNA Helicases; RNA, Double-Stranded; Receptors, Immunologic; Sendai virus; Signal Transduction; TNF Receptor-Associated Factor 6; Toll-Like Receptor 3; Toll-Like Receptors; Trans-Activators; Virus Replication
Immunology and Infectious Disease | Life Sciences | Medicine and Health Sciences
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.
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Citation: J Immunol. 2005 Oct 15;175(8):5260-8.