Signal transducer and activator of transcription 2 (Stat2) is a critical signaling protein involved in mediating interferon-alpha/beta (IFN-alpha/beta) responses. Using site-directed mutagenesis in conjunction with gene microarray and biologic studies, we have previously demonstrated that in addition to Stat2 functioning as a transactivator of transcription of a subset of IFN-inducible genes (ISG), Stat2-DNA binding mediates the transcriptional activation of other ISGs required for IFN-inducible antiviral and growth inhibitory responses. Among these, two candidate genes identified were Jun-D (JUND) and claudin-4 (CLDN4). To further explore the role of JUND and CLDN4 in IFN responses, we conducted knockdown studies using siRNA specific for either JUND or CLDN4 in 2fTGH fibroblast cells, and consistent with cells expressing the DNA-binding mutant of Stat2 (U6A-2VV-II), siRNA-mediated knockdown resulted in cells that exhibited reduced antiproliferative and antiviral responses to IFN. Our data suggest that JUND and CLDN4 are critical mediators of the antiproliferative and antiviral effects of type I IFNs and further confirm the functional importance of the DNA-binding domain of Stat2.