Stage-specific modulation of IFN-regulatory factor 4 function by Krüppel-type zinc finger proteins.
Optimal humoral responses depend on the activation of Ag-specific B cells, followed by their progression toward a fully differentiated phenotype. Acquisition of stage-appropriate patterns of gene expression is crucial to this differentiation program. However, the molecular mechanisms used by B cells to modulate gene expression as they complete their maturation program are poorly understood. IFN-regulatory factor 4 (IRF-4) plays a critical role in mature B cell function. Using the transcriptional regulation of the human B cell activation marker CD23 as a model system, we have previously demonstrated that IRF-4 is induced in response to B cell-activating stimuli and that it acts as a transactivator of CD23 gene expression. We have furthermore found that IRF-4 function can be blocked by B cell lymphomas 6 (BCL-6) protein, a Krüppel-type zinc finger repressor normally expressed in germinal center B cells. However, CD23 expression is known to be down-regulated in plasma cells despite high level expression of IRF-4 and the lack of BCL-6, suggesting that in plasma cells the IRF-4-mediated induction of CD23 is prevented by its interaction with a distinct repressor. In this set of studies, we demonstrate that IRF-4 interacts with B lymphocyte-induced maturation protein/positive regulatory domain I-binding factor 1 (Blimp1/PRD1-BF1), a Krüppel-type zinc finger protein whose expression correlates with terminal B cell differentiation. Functional studies indicate that Blimp1, like BCL-6, can block IRF-4-transactivating ability. These findings thus support a model whereby IRF-4 function is modulated in a stage-specific manner by its interaction with developmentally restricted sets of Krüppel-type zinc finger proteins.
Gupta
S
S
Department of Medicine, Columbia University, New York, NY 10032, USA.
Anthony
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A
Pernis
A B
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D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma / Q000378:metabolism*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic / Q000276:immunology; D017455:Receptors, IgE / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D016335:Zinc Fingers / Q000235:genetics / Q000276:immunology*; D000099218:Interferon Regulatory Factor-4
D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D000074462:Positive Regulatory Domain I-Binding Factor 1; D017455:Receptors, IgE; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099218:Interferon Regulatory Factor-4; C087042:PRDM1 protein, human