Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses.
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-beta 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.
Venkataraman
Thiagarajan
T
Department of Microbiology and Immunology and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL 33136, USA.
Valdes
Maikel
M
Elsby
Rachel
R
Kakuta
Shigeru
S
Caceres
Gisela
G
Saijo
Shinobu
S
Iwakura
Yoichiro
Y
Barber
Glen N
GN
D000818:Animals; D018188:Cardiovirus Infections / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D004686:Encephalomyocarditis virus / Q000276:immunology; D005260:Female; D007113:Immunity, Innate / Q000235:genetics; D000072640:Interferon-Induced Helicase, IFIH1; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface; D018353:Rhabdoviridae Infections / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology; D000097905:Roundabout Proteins
D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins; C503356:Ddx58 protein, mouse; C510592:Ifih1 protein, mouse