ZNF395 Is an Activator of a Subset of IFN-Stimulated Genes.
Activation of the interferon (IFN) pathway in response to infection with pathogens results in the induction of IFN-stimulated genes (ISGs) including proinflammatory cytokines, which mount the proper antiviral immune response. However, aberrant expression of these genes is pathogenic to the host. In addition to IFN-induced transcription factors non-IFN-regulated factors contribute to the transcriptional control of ISGs. Here, we show by genome wide expression analysis, siRNA-mediated suppression and Doxycycline-induced overexpression that the cellular transcription factor ZNF395 activates a subset of ISGs including the chemokines CXCL10 and CXCL11 in keratinocytes. We found that ZNF395 acts independently of IFN but enhances the IFN-induced expression of CXCL10 and CXCL11. Luciferase reporter assays revealed a requirement of intact NFκB-binding sites for ZNF395 to stimulate the CXCL10 promoter. The transcriptional activation of CXCL10 and CXCL11 by ZNF395 was abolished after inhibition of IKK by BMS-345541, which increased the stability of ZNF395. ZNF395 encodes at least two motifs that mediate the enhanced degradation of ZNF395 in response to IKK activation. Thus, IKK is required for ZNF395-mediated activation of transcription and enhances its turn-over to keep the activity of ZNF395 low. Our results support a previously unrecognized role of ZNF395 in the innate immune response and inflammation.
Institute of Virology, University of Cologne, Fürst-Pückler-Strasse 56, 50935 Cologne, Germany.
Linda
L
Schroeder
Institute of Virology, University of Cologne, Fürst-Pückler-Strasse 56, 50935 Cologne, Germany.
Christine
C
Herwartz
Institute of Virology, University of Cologne, Fürst-Pückler-Strasse 56, 50935 Cologne, Germany.
Darko
D
Jordanovski
Institute of Virology, University of Cologne, Fürst-Pückler-Strasse 56, 50935 Cologne, Germany.
Gertrud
0000-0002-0581-8122
G
Steger
D002460:Cell Line; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000097:blood / Q000235:genetics; D054371:Chemokine CXCL11 / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007372:Interferons / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010957:Plasmids; D011401:Promoter Regions, Genetic / Q000235:genetics; D011810:Quinoxalines / Q000494:pharmacology; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D004268:DNA-Binding Proteins; D007093:Imidazoles; D016898:Interferon-alpha; D016328:NF-kappa B; D011810:Quinoxalines; D034741:RNA, Small Interfering; D014157:Transcription Factors; C484332:ZNF395 protein, human; D007371:Interferon-gamma; D007372:Interferons; D051550:I-kappa B Kinase