MHC class II transactivator inhibits IL-4 gene transcription by competing with NF-AT to bind the coactivator CREB binding protein (CBP)/p300.
The MHC class II transactivator (CIITA) activates the expression of multiple genes involved in Ag presentation, but inhibits Th2-type cytokine production, including IL-4, during Th1 cell differentiation. Th1 cells derived from CIITA-deficient mice produce both Th1- and Th2-type cytokines, and the introduction of CIITA to Th2 cells down-regulates Th2-type cytokine gene transcription. Here we show that the IL-4 promoter is regulated by multiple protein-protein interactions among CIITA, NF-AT, and coactivator CBP/p300. The introduction of CBP/p300 and NF-AT enhances the IL-4 promoter activity, and this activation was repressed by CIITA. Furthermore, our data show that CIITA competes with NF-AT to bind CBP/p300 and that this competition dramatically influences transcriptional activation of the IL-4 promoter. We identified two domains of CIITA that interact with two distinct domains of CBP/p300 that are also recognized by NF-AT. CIITA mutants that retain the ability to interact with CBP/p300 are sufficient to inhibit NF-AT-mediated IL-4 gene expression.
Sisk
T J
TJ
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Gourley
T
T
Roys
S
S
Chang
C H
CH
D001667:Binding, Competitive / Q000235:genetics / Q000276:immunology; D050882:CREB-Binding Protein; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D015536:Down-Regulation / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D005802:Genes, MHC Class II / Q000276:immunology*; D006801:Humans; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017384:Sequence Deletion; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology
D004268:DNA-Binding Proteins; C083728:MHC class II transactivator protein; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D015847:Interleukin-4; D050882:CREB-Binding Protein; C494363:CREBBP protein, human