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CIITA is a transcriptional coactivator that is recruited to MHC class II promoters by multiple synergistic interactions with an enhanceosome complex

Muhlethaler-Mottet, Annick
Published in Genes and Development. 2000, vol. 14, no. 9, p. 1156-1166
Abstract By virtue of its control over major histocompatibility complex class II (MHC-II) gene expression, CIITA represents a key molecule in the regulation of adaptive immune responses. It was first identified as a factor that is defective in MHC-II deficiency, a hereditary disease characterized by the absence of MHC-II expression. CIITA is a highly regulated transactivator that governs all spatial, temporal, and quantitative aspects of MHC-II expression. It has been proposed to act as a non-DNA-binding transcriptional coactivator, but evidence that it actually functions at the level of MHC-II promoters was lacking. By means of chromatin immunoprecipitation assays, we show here for the first time that CIITA is physically associated with MHC-II, as well as HLA-DM, Ii, MHC-I, and beta(2)m promoters in vivo. To dissect the mechanism by which CIITA is recruited to the promoter, we have developed a DNA-dependent coimmunoprecipitation assay and a pull-down assay using immobilized promoter templates. We demonstrate that CIITA recruitment depends on multiple, synergistic protein-protein interactions with DNA-bound factors constituting the MHC-II enhanceosome. CIITA therefore represents a paradigm for a novel type of regulatory and gene-specific transcriptional cofactor.
Keywords B-Lymphocytes/ immunologyCell LineChromatin/physiologyDNA-Binding Proteins/genetics/metabolismGene Expression Regulation/ immunologyGenes, MHC Class IIHLA-D Antigens/ geneticsHLA-DR Antigens/geneticsHumansNuclear ProteinsPromoter Regions, GeneticRecombinant Proteins/metabolismTrans-Activators/ metabolismTransfectionTumor Cells, Cultured
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PMID: 10809673
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