Type I interferons (IFNs) stimulate transcription through a latent heterotrimeric transcription factor composed of tyrosinephosphorylated STAT1 and STAT2 and the DNA binding partner IRF9, with STAT2 contributing a critical transactivation domain. Human RVB1 and RVB2, which are highly conserved AAA ؉ ATP binding proteins contained in chromatin-remodeling complexes such as Ino80, SNF2-related CBP activator protein (SRCAP), and Tip60/NuA4, interacted with the transactivation domain of STAT2 in the nuclei of IFN-stimulated cells. RNA interference (RNAi) experiments demonstrated that RVB proteins were required for robust activation of IFN-␣-stimulated genes (ISGs). The requirement for RVB proteins was specific to IFN-␣/ STAT2 signaling; transcription of tumor necrosis factor alpha (TNF-␣)-and IFN-␥-driven genes was not affected by RVB1 depletion. Using RNAi-based depletion, we assessed the involvement of catalytic subunits of the RVB-containing Tip60, BRD8, Ino80, SRCAP, and URI complexes. No component other than RVB1/2 was uniquely required for ISG induction, suggesting that RVB1/2 functions as part of an as yet unidentified complex. Chromatin immunoprecipitation assays indicated that RVB1/2 was required for recruitment of RNA polymerase II (Pol II) to ISG promoters but was dispensable for STAT2 recruitment to chromatin. We hypothesize that an RVB1/2 chromatin-remodeling complex is required for efficient Pol II recruitment and initiation at ISG promoters and is recruited through interaction with the STAT2 transactivation domain.
Interferons (IFNs) are a family of pleiotropic cytokines primarily known for their ability to establish a potent antiviral state via modulation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signal transduction pathway. Alternatively, aberrant production of IFNs correlates with systemic autoimmunity, underscoring the importance of the stringent regulation of IFN responses. Type I IFNs activate the heterotrimeric transcription factor ISGF3, composed of tyrosine-phosphorylated STAT1 and STAT2 and an auxiliary DNA binding protein, IRF9. Following IFN stimulation, phosphorylated ISGF3 translocates into the nucleus, binds the interferon-stimulated response elements (ISREs) in the promoters of IFN-␣/-stimulated genes (ISGs), and rapidly and robustly induces the transcription of a large family of previously silent genes. ISGs subsequently influence multiple cellular pathways involved in innate immunity in order to protect against viral and bacterial replication, including modulation of cell stress responses, apoptosis, proliferation, translation, and innate and adaptive immune signaling (1). In the context of ISGF3, STAT2 contains an essential transactivation domain (TAD) that provides most of the transcriptional function to the transcription factor complex, whereas STAT1 and IRF9 confer DNA sequence specificity (2). Induction of IFN target genes provides a robust system for studying the molecular mechanisms underlying transcriptional regulation. However, little is...