Nonconventional initiation complex assembly by STAT and NF-kappaB transcription factors regulates nitric oxide synthase expression.
Transcriptional regulation of the Nos2 gene encoding inducible nitric oxide synthase (iNOS) requires type I interferon (IFN-I) signaling and additional signals emanating from pattern recognition receptors. Here we showed sequential and cooperative contributions of the transcription factors ISGF3 (a complex containing STAT1, STAT2, and IRF9 subunits) and NF-kappaB to the transcriptional induction of the Nos2 gene in macrophages infected with the intracellular bacterial pathogen Listeria monocytogenes. NF-kappaB preceded ISGF3 at the Nos2 promoter and generated a transcriptional memory effect by depositing basal transcription factor TFIIH with the associated CDK7 kinase for serine 5 phosphorylation of the RNA polymerase II (pol II) carboxyterminal domain (CTD). Subsequent to TFIIH deposition by NF-kappaB, ISGF3 attracted the pol II enzyme and phosphorylation at CTD S5 occurred. Thus, STATs and NF-kappaB cooperate through pol II promoter recruitment and the phosphorylation of its CTD, respectively, as a prerequisite for productive elongation of iNOS mRNA.
Farlik
Matthias
M
Max F. Perutz Laboratories, Department of Genetics, Microbiology and Immunobiology, University of Vienna, Dr. Bohr-Gasse 9/4, A1030 Vienna, Austria.
Reutterer
Benjamin
B
Schindler
Christian
C
Greten
Florian
F
Vogl
Claus
C
Müller
Mathias
M
Decker
Thomas
T
D000818:Animals; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases; D015971:Gene Expression Regulation, Enzymologic; D007370:Interferon Type I / Q000378:metabolism; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism; D008089:Listeria monocytogenes; D008088:Listeriosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012319:RNA Polymerase II; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D051758:Transcription Factor TFIIH; D000095043:Cyclin-Dependent Kinase-Activating Kinase
D007370:Interferon Type I; D050832:Interferon-Stimulated Gene Factor 3; D016328:NF-kappa B; D050791:STAT Transcription Factors; D051758:Transcription Factor TFIIH; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II; D000095043:Cyclin-Dependent Kinase-Activating Kinase