title: LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA.
abstract: The DExD/H box RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation associated gene-5 (mda-5) sense viral RNA in the cytoplasm of infected cells and activate signal transduction pathways that trigger the production of type I interferons (IFNs). Laboratory of genetics and physiology 2 (LGP2) is thought to influence IFN production by regulating the activity of RIG-I and mda-5, although its mechanism of action is not known and its function is controversial. Here we show that expression of LGP2 potentiates IFN induction by polyinosinic-polycytidylic acid [poly(I:C)], commonly used as a synthetic mimic of viral dsRNA, and that this is particularly significant at limited levels of the inducer. The observed enhancement is mediated through co-operation with mda-5, which depends upon LGP2 for maximal activation in response to poly(I:C). This co-operation is dependent upon dsRNA binding by LGP2, and the presence of helicase domain IV, both of which are required for LGP2 to interact with mda-5. In contrast, although RIG-I can also be activated by poly(I:C), LGP2 does not have the ability to enhance IFN induction by RIG-I, and instead acts as an inhibitor of RIG-I-dependent poly(I:C) signaling. Thus the level of LGP2 expression is a critical factor in determining the cellular sensitivity to induction by dsRNA, and this may be important for rapid activation of the IFN response at early times post-infection when the levels of inducer are low.
authors.affiliation: Division of Biomedical Sciences, St. George's, University of London, London, United Kingdom.
authors.forename: Kay S
authors.initials: KS
authors.lastname: Childs
authors.forename: Richard E
authors.initials: RE
authors.lastname: Randall
authors.forename: Stephen
authors.initials: S
authors.lastname: Goodbourn
mesh_terms: D001665:Binding Sites / Q000235:genetics; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C / Q000494:pharmacology; D011485:Protein Binding; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic; D015533:Transcriptional Activation / Q000187:drug effects; D020798:Two-Hybrid System Techniques; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; C502891:V protein, Paramyxovirus; D014764:Viral Proteins; C520569:DHX58 protein, human; 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; D011070:Poly I-C