Cooperative Transcriptional Activation of Antimicrobial Genes by STAT and NF-κB Pathways by Concerted Recruitment of the Mediator Complex

Sebastian Wienerroither; Priyank Shukla; Matthias Farlik; Andrea Majoros; Bernadette Stych; Claus Vogl; HyeonJoo Cheon; George R Stark; Birgit Strobl; Mathias Müller; Thomas Decker

doi:10.1016/j.celrep.2015.06.021

Cooperative Transcriptional Activation of Antimicrobial Genes by STAT and NF-κB Pathways by Concerted Recruitment of the Mediator Complex

Cell Rep. 2015 Jul 14;12(2):300-12. doi: 10.1016/j.celrep.2015.06.021. Epub 2015 Jul 2.

Authors

Affiliations

¹ Max F. Perutz Laboratories, University of Vienna, Drive Bohr-Gasse 9, 1030 Vienna, Austria.
² Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria.
³ CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria.
⁴ Department of Cancer Biology, Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
⁵ Max F. Perutz Laboratories, University of Vienna, Drive Bohr-Gasse 9, 1030 Vienna, Austria. Electronic address: thomas.decker@univie.ac.at.

Abstract

The transcriptional response to infection with the bacterium Listeria monocytogenes (Lm) requires cooperative signals of the type I interferon (IFN-I)-stimulated JAK-STAT and proinflammatory NF-κB pathways. Using ChIP-seq analysis, we define genes induced in Lm-infected macrophages through synergistic transcriptional activation by NF-κB and the IFN-I-activated transcription factor ISGF3. Using the Nos2 and IL6 genes as prime examples of this group, we show that NF-κB functions to recruit enzymes that establish histone marks of transcriptionally active genes. In addition, NF-κB regulates transcriptional elongation by employing the mediator kinase module for the recruitment of the pTEFb complex. ISGF3 has a major role in associating the core mediator with the transcription start as a prerequisite for TFIID and RNA polymerase II (Pol II) binding. Our data suggest that the functional cooperation between two major antimicrobial pathways is based on promoter priming by NF-κB and the engagement of the core mediator for Pol II binding by ISGF3.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Binding Sites
Histone Acetyltransferases / metabolism
Histone Methyltransferases
Histone-Lysine N-Methyltransferase / metabolism
Interferon-Stimulated Gene Factor 3 / genetics
Interferon-Stimulated Gene Factor 3 / metabolism
Interleukin-6 / genetics
Interleukin-6 / metabolism
Listeria monocytogenes / physiology
Macrophages / cytology
Macrophages / immunology
Macrophages / metabolism
Mediator Complex / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
NF-kappa B / genetics
NF-kappa B / metabolism*
Nitric Oxide Synthase Type II / genetics
Nitric Oxide Synthase Type II / metabolism
Protein Binding
Proto-Oncogene Proteins / antagonists & inhibitors
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
RNA Polymerase II / metabolism
STAT Transcription Factors / metabolism*
Signal Transduction
Transcription Factor TFIID / metabolism
Transcriptional Activation

Substances

Interferon-Stimulated Gene Factor 3
Interleukin-6
MEN1 protein, human
Mediator Complex
NF-kappa B
Proto-Oncogene Proteins
STAT Transcription Factors
Transcription Factor TFIID
Nitric Oxide Synthase Type II
Nos2 protein, mouse
Histone Methyltransferases
Histone-Lysine N-Methyltransferase
Histone Acetyltransferases
RNA Polymerase II