Repression by Homeoprotein Pitx1 of Virus-Induced Interferon A Promoters Is Mediated by Physical Interaction and trans Repression of IRF3 and IRF7

Abstract

Interferon A (IFN-A) genes are differentially expressed after virus induction. The differential expression of individual IFN-A genes is modulated by the specific transcription activators IFN regulatory factor 3 (IRF3) and IRF-7 and the homeoprotein transcription repressor Pitx1. We now show that repression by Pitx1 does not appear to be due to the recruitment of histone deacetylases. On the other hand, Pitx1 inhibits the IRF3 and IRF7 transcriptional activity of the IFN-A11 and IFN-A5 promoters and interacts physically with IRF3 and IRF7. Pitx1 trans-repression activity maps to specific C-terminal domains, and the Pitx1 homeodomain is involved in physical interaction with IRF3 or IRF7. IRF3 is able to bind to the antisilencer region of the IFN-A4 promoter, which overrides the repressive activity of Pitx1. These results indicate that interaction between the Pitx1 homeodomain and IRF3 or IRF7 and the ability of the Pitx1 C-terminal repressor domains to block IFN-A11 and IFN-A5 but not IFN-A4 promoter activities may contribute to our understanding of the complex differential transcriptional activation, repression, and antirepression of the IFN-A genes.

We thank J. Hiscott, J. S. Pagano, A. Harel-Bellan and T. Taniguchi for kindly providing IRF3, IRF7, HDAC1 cDNA, and IRF1/IRF2 antibodies respectively. We are grateful to E. Bonnefoy for discussion and encouragements, and E. Prieto for photographs. This work at UPR-2228 was supported by the Centre National de la Recherche Scientifique (CNRS), the Université René Descartes Paris V and grants from the Association de Recherche contre le Cancer (ARC, contrat 9994), Ligue Régionale contre le Cancer and CNRS PCV program (PCV098-33). M-L Island is a recipient of the Association de Recherche contre le Cancer and T Mesplede is a recipient of the Ligue Nationale contre le Cancer.