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Type I interferon (IFN)-dependent STAT1 and STAT2 activation requires specific tyrosine residues (337Y and 512Y) located in the cytoplasmic domain of IFNAR-2c, the beta-subunit of the human type I IFN receptor. To identify STAT activation-independent induction of ISGs, we used a mutant cell line in which both 337Y and 512Y were substituted with phenylalanine (337F512F or FF mutant). In these cells, type I IFN failed to activate STAT1, STAT2, and STAT3 did not induce well-characterized ISGs and did not exert antiviral or antiproliferative effects. Using Oligonucleotide array (Affymetrix) analysis, we showed that interferon regulatory factor-9 (IRF-9) was the only gene induced by IFN-beta in FF cells. Transient transfection analysis using an IRF-9 promoter-reporter luciferase construct in FF cells confirmed induction of the IRF-9 transcription unit by IFN-beta. EMSA analysis using an IFN-stimulated response element (ISRE)-like sequence on the IRF-9 promoter detected 2 novel DNA-binding complexes induced in nuclear extracts of IFN-beta-treated FF cells. Supershift experiments identified the proteins IRF-1 and C/EBP-beta in the complex. These studies provide the first evidence that signaling pathways leading to gene transcription are activated by IFN-beta independent of STAT phosphorylation.

STAT-Phosphorylation–Independent Induction of Interferon Regulatory Factor-9 by Interferon-β