Configuration of the interferon-alpha/beta receptor complex determines the context of the biological response.
Constituents of the Type 1 interferon (IFN) receptor (IFNABR) identified to date include the alpha and beta transmembrane subunits and the associated intracellular kinases, Jak 1 and Tyk 2. In this report, we demonstrate that a human cell type that expresses both subunits of IFNABR, together with Jak 1 and Tyk 2, exhibits a limited binding capacity for and is only partially sensitive to the effects of IFN-alpha/beta, despite adequate levels of the cytoplasmic transcription factors Stat1, Stat2, and Stat3. Specifically, a low affinity interaction between IFN-alpha/beta and cell surface receptors results in ISGF3 (Stat1:2) activation and an antiviral response, yet no IFN-inducible growth inhibition. Using a panel of murine cells that are variably configured with respect to the human IFNABR-alpha/beta subunits, we provide evidence that an additional component(s) encoded on human chromosome 21 is required to confer high affinity binding and IFN-inducible growth inhibition to cells that express the alpha and beta subunits of the IFNABR. The data indicate that transcriptional activation that leads to an antiviral response is mediated by IFN-alpha/beta activation of IFNABR-alpha and IFNABR-beta in the context of a low affinity interaction, yet a high affinity interaction is necessary for signal transducing events that mediate growth inhibition. We provide evidence that the extent of ISGF3 activation correlates directly with the magnitude of an antiviral but not a growth inhibitory response.
Ghislain
J
J
Department of Microbiology, University of Toronto, Ontario, Canada.
Sussman
G
G
Goelz
S
S
Ling
L E
LE
Fish
E N
EN
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002891:Chromosomes, Human, Pair 21; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D005434:Flow Cytometry; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D053613:Janus Kinase 1; D007700:Kinetics; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D017471:Receptors, Interferon / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D017931:DNA Primers; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D007370:Interferon Type I; D016898:Interferon-alpha; D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D011506:Proteins; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494080:Stat1 protein, mouse; C494085:Stat2 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016899:Interferon-beta; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C499356:Tyk2 protein, mouse; D015088:2',5'-Oligoadenylate Synthetase