PHOSPHORYLATION EVENTS MODULATE THE ABILITY OF INTERFERON CONSENSUS SEQUENCE BINDING-PROTEIN TO INTERACT WITH INTERFERON REGULATORY FACTORSAND TO BIND DNA

Two families of transcription factors mediate interferon (IFN) signali ng, The first family, signal transducers and activators of transcripti on (STATs), is activated within minutes of IFN treatment. Specific pho sphorylation events lead to their translocation to the nucleus, format ion of transcriptional complexes, and the induction of the second fami ly of transcription factors termed interferon regulatory factors (IRFs ). Interferon consensus sequence binding protein (ICSBP) is a member o f IRF family that is expressed only in cells of the immune system and acts as a transcriptional repressor. ICSBP binds DNA through the assoc iation with other transcription factors such as IRF-1 or IRF-2. In thi s communication, the domain that is involved in protein-protein intera ctions was mapped to the carboxyl terminus of ICSBP. This domain is al so important for mediating ICSBP repressing activity. In vitro studies demonstrated that direct binding of ICSBP to DNA is prevented by tyro sine (Tyr) phosphorylation. Yet, Tyr-phosphorylated ICSBP can bind tar get DNA only through the association with IRF-2 and IRF-1. This type o f phosphorylation is essential for the formation of heterocomplexes. T yr-phosphorylated ICSBP and IRF-2 are detected in expressing cells con stitutively, and Tyr-phosphorylated IRF-1 is induced by IFN-gamma. The se results strongly suggest that like the STATs, the IRFs are also mod ulated by Tyr phosphorylation that affects their biological activities .