Combinatorial Association and Abundance of Components of Interferon-Stimulated Gene Factor 3 Dictate the Selectivity of Interferon Responses

Genes containing the interferon-stimulated response element (ISRE) enhancer have been characterized as transcriptionally responsive primarily to type I interferons (IFNα/β). Induction is due to activation of a multimeric transcription factor, interferon-stimulated gene factor 3 (ISGF3), which is activated by IFNα/β but not by IFNγ. We found that ISRE-containing genes were induced by IFNγ as well as by IFNα in Vero cells. The IFNγ response was dependent on the ISRE and was accentuated by preexposure of cells to IFNα, a treatment that increases the abundance of ISGF3 components. Overexpression of ISGF3 polypeptides showed that the IFNγ response depended on the DNA-binding protein ISGF3γ(p48) as well as on the 91-kDa protein STAT91 (Stat1α). The transcriptional response to IFNα required the 113-kDa protein STAT113 (Stat2) in addition to STAT91 and p48. Mutant fibrosarcoma cells deficient in each component of ISGF3 were used to confirm that IFNγ induction of an ISRE reporter required p48 and STAT91, but not STAT113. A complex containing p48 and phosphorylated STAT91 but lacking STAT113 bound the ISRE in vitro. IFNγ-induced activation of this complex, preferentially formed at high concentrations of p48 and STAT91, may explain some of the overlapping responses to IFNα and IFNγ.