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* Department of Microbiology and Immunology and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL 33136; and
Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan
The DExD/H box RNA helicase retinoic acid-inducible gene I (RIG-I) and the melanoma differentiation-associated gene 5 (MDA5) are key intracellular receptors that recognize virus infection to produce type I IFN. A third helicase gene, Lgp2, is homologous to Rig-I and Mda5 but lacks a caspase activation and recruitment domain. We generated Lgp2-deficient mice and report that the loss of this gene greatly sensitizes cells to cytosolic polyinosinic/polycytidylic acid-mediated induction of type I IFN. However, negative feedback inhibition of IFN-
transcription was found to be normal in the absence of LGP2, indicating that LGP2 is not the primary negative regulator of type I IFN production. Our data further indicate that Lgp2–/– mice exhibited resistance to lethal vesicular stomatitis virus infection, a virus whose replicative RNA intermediates are recognized specifically by RIG-I rather than by MDA5 to trigger the production of type I IFN. However, mice lacking LGP2 were observed to exhibit a defect in type I IFN production in response to infection by the encephalomyocarditis virus, the replication of which activates MDA5-dependent innate immune responses. Collectively, our data indicate a disparate regulatory role for LGP2 in the triggering of innate immune signaling pathways following RNA virus infection.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 T.V. and M.V. contributed equally to this work.
2 Address correspondence and reprint requests to Dr. Glen N. Barber, University of Miami School of Medicine, 1550 Northwest 10th Avenue (M710), Papanicolaou Building, Room 511, Miami, FL 33136. E-mail address: gbarber{at}med.miami.edu
3 Abbreviations used in this paper: TIR, Toll/IL-1R; IRAK, IL-1R-associated kinase; IRF, IFN-regulatory factor; DC, dendritic cell; BMDC, bone marrow-derived DC; CARD, caspase activation and recruitment domain; EMCV, encephalomyocarditis virus; FADD, Fas-associated death domain protein; IPS-1, IFN- promoter stimulator 1; i.n., intranasal(ly); Luc, luciferase; MDA5, melanoma differentiation-associated gene 5; MEF, mouse embryonic fibroblast; MOI, multiplicity of infection; poly(I:C), polyinosinic/polycytidylic acid; qRT-PCR, quantitative RT-PCR; RIG-I, retinoic acid-inducible gene I; VSV, vesicular stomatitis virus; WT, wild type.
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