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

Abstract EN

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.