Viral targeting of TFIIB impairs de novo polymerase II recruitment and affects antiviral immunity.

Darya A Haas,Andreas Pichlmair,Katharina Geiger,Arno Meiler,Georg Kochs,Ellen Preuss,Carola Vogt,Peter Palese

doi:10.1371/journal.ppat.1006980

Abstract

Viruses have evolved a plethora of mechanisms to target host antiviral responses. Here, we propose a yet uncharacterized mechanism of immune regulation by the orthomyxovirus Thogoto virus (THOV) ML protein through engaging general transcription factor TFIIB. ML generates a TFIIB depleted nuclear environment by re-localizing it into the cytoplasm. Although a broad effect on gene expression would be anticipated, ML expression, delivery of an ML-derived functional domain or experimental depletion of TFIIB only leads to altered expression of a limited number of genes. Our data indicate that TFIIB is critically important for the de novo recruitment of Pol II to promoter start sites and that TFIIB may not be required for regulated gene expression from paused promoters. Since many immune genes require de novo recruitment of Pol II, targeting of TFIIB by THOV represents a neat mechanism to affect immune responses while keeping other cellular transcriptional activities intact. Thus, interference with TFIIB activity may be a favourable site for therapeutic intervention to control undesirable inflammation.

Highlights

Transcription of DNA by RNA polymerase II (Pol II) is central to gene expression and subject to regulation at multiple levels
We show that the orthomyxovirus Thogoto virus impairs activity of general transcription factor IIB (TFIIB)
Since the innate immune system heavily relies on genes that require de novo recruitment of the polymerase complex, targeting of TFIIB represents a neat mechanism to broadly affect antiviral immunity

Summary

Introduction

Transcription of DNA by RNA polymerase II (Pol II) is central to gene expression and subject to regulation at multiple levels. The first step includes subunits of Pol II and general transcription factors (GTFs), which sequentially assemble into a preinitiation complex (PIC) that recognizes promoter regions on DNA and responds to regulatory signals in order to start mRNA synthesis [2]. GTFs include Transcription Factor (TF) IIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH [3]. TFIID nucleates PIC assembly by binding promoter sequences through its TATA binding protein (TBP subunit) [4] and recruits TFIIB, which mediates the association of Pol II with the promoter [5]. TFIIE and TFIIH unwind DNA at the promoter for the initiation of transcription [6]. Pol II is released from the promoter to enable downstream transcription, while most of the GTFs dissociate from the promoter [7]

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Discussion

Conclusion