ZNF395 Is an Activator of a Subset of IFN-Stimulated Genes

Mediators Inflamm. 2017;2017:1248201. doi: 10.1155/2017/1248201. Epub 2017 Feb 21.


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.

MeSH terms

  • Cell Line
  • Cells, Cultured
  • Chemokine CXCL10 / blood
  • Chemokine CXCL10 / genetics
  • Chemokine CXCL11 / blood
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors
  • I-kappa B Kinase / metabolism
  • Imidazoles / pharmacology
  • Interferon-alpha / pharmacology
  • Interferon-gamma / pharmacology
  • Interferons / pharmacology*
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Plasmids
  • Promoter Regions, Genetic / genetics
  • Quinoxalines / pharmacology
  • RNA, Small Interfering
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline
  • Chemokine CXCL10
  • Chemokine CXCL11
  • DNA-Binding Proteins
  • Imidazoles
  • Interferon-alpha
  • NF-kappa B
  • Quinoxalines
  • RNA, Small Interfering
  • Transcription Factors
  • ZNF395 protein, human
  • Interferon-gamma
  • Interferons
  • I-kappa B Kinase