Abstract
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.
Highlights
The interferon- (IFN-) mediated innate immune response is the first line defense against invading pathogens
We show by genome wide expression analysis, Small interfering RNAs (siRNAs)-mediated suppression and Doxycyclineinduced overexpression that the cellular transcription factor ZNF395 activates a subset of IFN-stimulated genes (ISGs) including the chemokines CXCL10 and CXCL11 in keratinocytes
RTS3b cells were transfected with control siRNA or with a pool of four siRNAs targeting ZNF395 to suppress the endogenous level of ZNF395. 18 h later the cells were incubated in medium containing IFNα for 6 h and total cellular RNA was isolated and transcribed to c-DNA
Summary
The interferon- (IFN-) mediated innate immune response is the first line defense against invading pathogens. Secreted type I IFNs bind to the ubiquitously expressed IFNA receptor (IFNAR) on the same cells as well as on neighboring cells and initiate a signaling cascade leading to the activation and phosphorylation of the signal transducers and activators of transcription (STAT) STAT1 and STAT2. This enables complex formation with IRF9 to build the trimeric transcription factor ISGF3 which binds to the IFN-stimulated response element (ISRE), present in the upstream region of ISGs. ISGF3 activates the transcription of a set of several hundred ISRE driven ISGs which have antiviral and proinflammatory activity. Dysregulation of IFN production and signaling results in autoimmune disorders such as systemic lupus erythematosus (reviewed in [1])
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