The Human RVB Complex Is Required for Efficient Transcription of Type I Interferon-Stimulated Genes

Abstract

Type I interferons (IFNs) stimulate transcription through a latent heterotrimeric transcription factor composed of tyrosine-phosphorylated 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-α-stimulated genes (ISGs). The requirement for RVB proteins was specific to IFN-α/STAT2 signaling; transcription of tumor necrosis factor alpha (TNF-α)- and IFN-γ-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.

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SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01562-12.

ACKNOWLEDGMENTS

We thank William Y. Tsang and Jia Meng for technical assistance, Isabelle Marié and Susan Logan for helpful discussions, and Anindya Dutta, Yixian Zheng, and Bruno Amati for gifts of reagents.

This work was supported by grants from the NIH (R01AI28900, U54AI057157, and T32CA009161).