Antiviral activities of the soluble extracellular domains of type I interferon receptors.
Alternative splicing leads to the expression of multiple isoforms of the subunits (IFNAR1 and IFNAR2) of the type I IFN receptor. Here we describe two transcripts representing extracellular forms of ovine IFNAR1 and show that soluble extracellular forms of both IFNAR2 and IFNAR1, prepared in recombinant form in Escherichia coli, have antiviral (AV) activity in the absence of IFN. Exposure of Madin-Darby bovine kidney cells to the extracellular domain (R2E) of IFNAR2 at concentrations as low as 10 nM afforded complete protection against vesicular stomatitis virus and led to the rapid activation of the transcription factors ISGF3 and GAF. Although R2E can bind IFN (K(d) approximately 70 nM), activity was observed irrespective of whether or not ligand was present. R2E was inactive on mouse L929 cells but active on L929 cells expressing a membraneanchored, ovine/human chimeric IFNAR2 with an ovine extracellular domain. The data suggest that AV activity is conferred by the ability of soluble R2E to associate with the transfected IFNAR2 subunit rather than resident murine IFNAR1. Soluble extracellular forms of IFNAR1 have lower AV activity than R2E on Madin-Darby bovine kidney cells but are less species-specific and protect wild-type L929 cells as efficiently as the transfected cell line, presumably by interacting with one of the murine receptor subunits.
Han
C S
CS
Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA.
Chen
Y
Y
Ezashi
T
T
Roberts
R M
RM
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D001483:Base Sequence; D002417:Cattle; D002460:Cell Line; D003001:Cloning, Molecular; D003432:Cross-Linking Reagents; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000378:metabolism; D005110:Extracellular Space; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D012756:Sheep; D012995:Solubility; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000254:growth & development*
D000998:Antiviral Agents; D003432:Cross-Linking Reagents; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C507964:IFNAR1 protein, human; C508033:IFNAR2 protein, human; C494227:IRF9 protein, human; C508032:Ifnar1 protein, mouse; C508034:Ifnar2 protein, mouse; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; C494228:Isgf3g protein, mouse; D008565:Membrane Proteins; D017471:Receptors, Interferon; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C120411:interferon receptor, type II; D053633:Receptor, Interferon alpha-beta