IFN regulatory factor-2 cooperates with STAT1 to regulate transporter associated with antigen processing-1 promoter activity.
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-gamma 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-gamma 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-gamma activate the expression of TAP1 via a new mechanism that involves functional cooperation between STAT1 and IRF-2 on the TAP1 promoter.
Rouyez
Marie-Christine
MC
Department of Hematology, Institut Cochin, Paris, France.
Lestingi
Marta
M
Charon
Martine
M
Fichelson
Serge
S
Buzyn
Agnès
A
Dusanter-Fourt
Isabelle
I
D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D050836:Interferon Regulatory Factor-2; D007371:Interferon-gamma / Q000494:pharmacology; D008533:Megakaryocytes / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D050794:STAT1 Transcription Factor; D013926:Thrombopoietin / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; C494229:IRF2 protein, human; D050836:Interferon Regulatory Factor-2; D012333:RNA, Messenger; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C477327:transporter associated with antigen processing (TAP); D007371:Interferon-gamma; D013926:Thrombopoietin