Identification and characterization of an interferon (IFN)-stimulated response element-IFN-stimulated gene factor 3-independent signaling pathway for IFN-alpha.

Transcriptional activation of genes containing the interferon (IFN)-stimulated response element (ISRE) by IFN-alpha is known to be mediated through the post-translational activation of IFN-stimulated gene factor 3 (ISGF3) and its subsequent interactions with the ISRE. We have identified an ISRE-ISGF3-independent signaling pathway used by IFN-alpha for the induction of the IFN regulatory factor 1 (IRF-1) gene. A minimal functional promoter of the IRF-1 gene does not contain an ISRE, but we have shown that transcription of the IRF-1 gene is activated by IFN-alpha in cell lines that do not produce ISGF3 activity due to the absence of functional ISGF3-gamma (p48) polypeptide. This ISRE-ISGF3-independent pathway for IFN-alpha signaling involves a cis-acting enhancer element located in the IRF-1 promoter, termed the inverted repeat (IR) element, and its cognate trans-acting factor, IR-binding factor alpha (IRBF-alpha). IFN-gamma also activates a transcription factor(s) that forms a different complex (IRBF-gamma) with the IR element. Protein-tyrosine kinase (tyk2) activity is required for the induction of IRBF-alpha, but not IRBF-gamma. The p91 subunit of ISGF3 is necessary for the formation of both IRBF-alpha and IRBF-gamma.