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The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I.

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.

Pubmed ID: 16210631

Authors

  • Rothenfusser S
  • Goutagny N
  • DiPerna G
  • Gong M
  • Monks BG
  • Schoenemeyer A
  • Yamamoto M
  • Akira S
  • Fitzgerald KA

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Data

October 15, 2005

Associated Grants

None

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Animals
  • Antigens, Differentiation
  • Cell Line
  • Humans
  • Membrane Transport Proteins
  • Mice
  • Mice, Knockout
  • Myelin Proteins
  • Myelin and Lymphocyte-Associated Proteolipid 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