Interaction of the transcriptional activator Stat-2 with the type I interferon receptor

Binding of interferon-α (IFNα) to the multisubunit type I IFN receptor (IFNR) induces activation of the Tyk-2 and Jak-1 kinases and tyrosine phosphorylation of multiple signaling elements, including the Stat proteins that form the ISGF3α complex. Although Jak kinases are required for IFNα- dependent activation of Stats, the mechanisms by which Stats interact with these kinases are not known. We report that Stat-2 associates with β(s) subunit of the type I IFN receptor in an interferon-dependent manner. This association is rapid, occurring within 1 min of interferon treatment of cells, and is inducible by various type I (α, β, ω) but not type II (γ) IFNs. The kinetics of Stat-2-IFNR association are similar to the kinetics of phosphorylation of Stat-2, suggesting that during its binding to the type I IFNR, Stat-2 acts as a substrate for interferon-dependent tyrosine kinase activity. These findings support the hypothesis that the type I IFNR acts as an adaptor, linking Stat proteins to Jak kinases. Interaction of Stat-2 with the β(s) subunit of the type I IFNR may be a critical signaling event, required for the formation of the ISGF3α complex and downstream transcription of interferon-stimulated genes.