INTERFERON REGULATORY FACTOR-3 AND CREB-BINDING PROTEIN P300 ARE SUBUNITS OF DOUBLE-STRANDED RNA-ACTIVATED TRANSCRIPTION FACTOR DRAF1/

Cells respond to viral infection or double-stranded RNA with the trans criptional induction of a subset of alpha/beta interferon-stimulated g enes by a pathway distinct from the interferon signal pathway. The tra nscriptional induction is mediated through a DNA sequence containing t he alpha/beta interferon-stimulated response element (ISRE). We previo usly identified a novel transcription factor, designated double-strand ed RNA-activated factor 1 (DRAF1), that recognizes this response eleme nt. The DNA-binding specificity of DRAF1 correlates with transcription al induction, thereby distinguishing it as a positive regulator of alp ha/beta interferon-stimulated genes. Two of the components of DRAF1 ha ve now been identified as interferon regulatory factor 3 (IRF-3) and t he transcriptional coactivator CREB-binding protein (CBP)/p300. We dem onstrate that IRF-3 preexists in the cytoplasm of uninfected cells and translocates to the nucleus following viral infection. Translocation of IRF-3 is accompanied by an increase in serine and threonine phospho rylation. Coimmunoprecipitation analyses of endogenous proteins demons trate an association of IRF-3 with the transcriptional coactivators CB P and p300 only subsequent to infection. In addition, antibodies to th e IRF-3, CBP, and p300 molecules react with DRAF1 bound to the ISRE ta rget site of induced genes. The cellular response that leads to DRAF1 activation and specific gene expression may serve to increase host sur vival during viral infection.