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IFN Regulatory Factor-2 Cooperates with STAT1 to Regulate Transporter Associated with Antigen Processing-1 Promoter Activity¹

Marie-Christine Rouyez^*, Marta Lestingi^*, Martine Charon^*, Serge Fichelson^*, Agnès Buzyn and Isabelle Dusanter-Fourt^2,*

Departments of ^* Hematology and Immunology, Institut Cochin, Paris, France

Class I MHC complexes (MHC_I) are essential in mediating immune response. The transport of antigenic peptides (TAP) to MHC_I and the stable expression of MHC_I on the cell surface require the presence of a dedicated TAP. In this study we report that IFN- and thrombopoietin (TPO) strongly increase TAP1 protein expression in megakaryocytes, followed by an enhanced expression of MHC_I on the cell surface. This expression parallels the enhanced TAP1 promoter activity and TAP1 mRNA expression, which are independent of protein synthesis. We also show that this cytokine-dependent expression of TAP1 transcripts depends on STAT1 and IFN regulatory factor-2 (IRF-2), but not on IRF-1, and provide evidence that IRF-2 constitutively binds to the TAP1 gene promoter and enhances TAP1 promoter activity. We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN- target cells tested. Interaction of IRF-2 and STAT1 on the promoter depends on the DNA-binding domain of IRF-2. Overall, our data indicate that TPO and IFN- activate the expression of TAP1 via a new mechanism that involves functional cooperation between STAT1 and IRF-2 on the TAP1 promoter.

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