Essential and non‐redundant roles of p48 (ISGF3γ) and IRF‐1 in both type I and type II interferon responses, as revealed by gene targeting studies

Background: Interferons (IFNs) are a class of cytokines which confer cellular resistance against viral infections. Type I (IFN‐α and ‐β) and type II (IFN‐γ) IFNs utilize distinct receptors, the stimulation of which results in the induction of downstream target genes. These target genes usually contain within their promoter region an IFN responsive element, termed ISRE (IFN stimulated response element) which binds a heterotrimeric transcription factor, ISGF3 (IFN‐stimulated gene factor 3) consisting of p48 (ISGF3 γ), Stat1 (Signal transducers and activators of transcription‐1; α or β), and Stat2. The ISRE sequence overlaps with that of IRF‐E which binds another IFN‐inducible factor, IRF‐1 (IFN regulatory factor‐1). Results: We generated mice lacking p48 by gene targeting. We show that p48 plays an essential role in both type I and type II IFN responses; activation of IFN‐inducible genes and establishment of the antiviral state by IFN‐α or ‐γ are both severely impaired, and ISRE‐binding activities induced by both IFNs are absent in the p48‐negative embryonic fibroblasts (EFs). Furthermore, we generated mice deficient for both p48 and IRF‐1 and found that at least one IFN‐inducible gene is dependent on both factors. Conclusions: p48 and IRF‐1 do not perform redundant functions in the cell, but rather complement one another in both type I and II IFN responses.