The POU Transcription Factor Oct-1 Represses Virus-Induced Interferon A Gene Expression

Abstract

Alpha interferon (IFN-␣Alpha interferon (IFN-␣) and IFN-␤ are able to interfere with viral infection. They exert a vast array of biologic functions, including growth arrest, cell differentiation, and immune system regulation (for reviews, see references 28 and 51). This regulation extends from innate immunity to cellular and humoral adaptive immune responses. A strict control of expression is needed to prevent detrimental effects of unregulated IFN. IFN transcription is coordinately induced in human and mouse cells infected by virus. Multiple IFN-A subtypes exhibit differences in expression of their individual mRNAs.IFN-A transcription is regulated by a number of different activators and repressors. Among these factors, the interferon regulatory factors (IRFs) play an important role in the stimulation of cellular antiviral defense mechanisms in different cell types. IRFs regulate transcription by interacting with gene promoter sequences. Until now, repressors involved in negative regulation of the IFN-A genes have not been well characterized (for a review, see reference 29). We have shown that in addition to substitutions in proximal virus responsive element A (VRE-A) (2), the low expression levels of the IFN-A11 and IFN-A5 genes after virus induction are also due to the presence of a distal negative regulatory element (DNRE) of 20 bp, which is delimited upstream of VRE-A (20, 25, 26). The analysis of the DNRE responsible for the virus-induced transcription repression of some IFN-A promoters led us to study the homeodomain transcription factor Pitx1 (25). Upon virus induction, Pitx1 negatively regulates the transcription of DNREcontaining IFN-A11 and IFN-A5 promoters (20,25). We have recently shown that Pitx1 inhibits the IRF-3 and IRF-7 transcription activation of the IFN-A11 and IFN-A5 promoters and interacts physically with .Here we show that the POU protein Oct-1 binds in vitro to the DNRE and in vivo to the endogenous IFN-A11 promoter in mock-induced and induced cells. Furthermore, Oct-1 represses IFN-A11 expression upon IRF overexpression. Moreover, we show that Oct-1-deficient MEFs exhibit increased in vivo IFN-A gene expression and increased antiviral activity. Finally, the IFN-A expression pattern is modified in Oct-1-deficient MEFs. The broad representation of effective and potent octamer-like sequences within IFN-A promoters suggests an important role for Oct-1 in IFN-A regulation. We suggest this could have implications in IFN-␣-based combinatorial therapies. MATERIALS AND METHODSDNA transfection, viral induction, and transfection assays. Murine L929 cells were transfected by the standard calcium phosphate precipitation method as previously described (26). Newcastle disease virus (NDV) induction was carried out 24 h later. The mock-induced cells were set up as described above except that no NDV was added. Cells were harvested 24 h postinduction, and cytoplasm extracts were prepared. Luciferase activity was measured in cell lysates by using commercial reagents (Promega). Transfection efficiency was de...

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