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The transcription factor MafB antagonizes antiviral responses by blocking recruitment of coactivators to the transcription factor IRF3

Nature Immunology volume 11, pages 743–750 (2010)Cite this article

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Abstract

Viral infection induces type I interferons (IFN-α and IFN-β) that recruit unexposed cells in a self-amplifying response. We report that the transcription factor MafB thwarts auto-amplification by a metastable switch activity. MafB acted as a weak positive basal regulator of transcription at the IFNB1 promoter through activity at transcription factor AP-1–like sites. Interferon elicitors recruited the transcription factor IRF3 to the promoter, whereupon MafB acted as a transcriptional antagonist, impairing the interaction of coactivators with IRF3. Mathematical modeling supported the view that prepositioning of MafB on the promoter allows the system to respond rapidly to fluctuations in IRF3 activity. Higher expression of MafB in human pancreatic islet beta cells might increase cellular vulnerability to viral infections associated with the etiology of type 1 diabetes.

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Figure 1: MafB negatively regulates type I interferon induction.
Figure 2: Deletion of Mafb facilitates the induction of type I interferon.
Figure 3: MafB interferes with the activity of IRF3 and IRF7.
Figure 4: Mechanisms underlying the MafB-mediated suppression of type I interferon induction.
Figure 5: Regulation of MafB expression in response to pathogen triggers.
Figure 6: Roles of MafB in pancreatic beta cells.

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Acknowledgements

We thank J. Darga for assistance with automated assays and high-throughput screens; R. Niedra, N. Lu and W. Zhou for experimental help; the Seed and Xavier groups for sharing reagents and information; S. Takahashi and M. Hamada (University of Tsukuba) and D. Engel (University of Michigan) for Mafb-deficient MEFs and discussions; S. Whelan (Harvard Medical School) for VSV-Luc; T. Fujita (Kyoto University) for the CBP construct; J.-i. Miyazaki (Osaka University) and D.F. Steiner (University of Chicago) for MIN6 cells; C. Vanderburg for assistance with laser-capture microdissection; and M. Wathelet, R. Lin, S. Han and H. Lee for discussions.

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Authors and Affiliations

  1. Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA

    Hwijin Kim & Brian Seed

  2. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA

    Hwijin Kim & Brian Seed

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H.K. designed and did experiments and wrote the manuscript; B.S. designed and supervised research and wrote the manuscript.

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Correspondence to Brian Seed.

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Kim, H., Seed, B. The transcription factor MafB antagonizes antiviral responses by blocking recruitment of coactivators to the transcription factor IRF3. Nat Immunol 11, 743–750 (2010). https://doi.org/10.1038/ni.1897

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