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GCN5 and ADA Adaptor Proteins Regulate Triiodothyronine/GRIP1 and SRC-1 Coactivator-Dependent Gene Activation by the Human Thyroid Hormone Receptor

Samuel Lunenfeld Research Institute (M.A., Y.-F.Y., P.G.W.) and Departments of Medicine, Pediatrics, and Otolaryngology (P.G.W.) University of Toronto Medical School Divisions of Head and Neck Oncology and Endocrinology of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
The Wistar Institute (N.A.B., S.L.B.) Philadelphia, Pennsylvania 19104
Centre de Recherche (M.V.G.) Hotel-Dieu de Quebec Université Laval Quebec G1R 2J6, Canada
LifeSensors Inc. (T.R.B.) Malvern, Pennsylvania 19355
Department of Biochemistry & Biophysics (T.R.B.) University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 19104-6509

We have used yeast genetics and in vitro protein-protein interaction experiments to explore the possibility that GCN5 (general control nonrepressed protein 5) and several other ADA (alteration/deficiency in activation) adaptor proteins of the multimeric SAGA complex can regulate T₃/GRIP1 (glucocorticoid receptor interacting protein 1) and SRC-1 (steroid receptor coactivator-1) coactivator-dependent activation of transcription by the human T₃ receptor ß1 (hTRß1). Here, we show that in vivo activation of a T₃/GRIP1 or SRC-1 coactivator-dependent T₃ hormone response element by hTRß1 is dependent upon the presence of yeast GCN5, ADA2, ADA1, or ADA3 adaptor proteins and that the histone acetyltransferase (HAT) domains and bromodomain (BrD) of yGCN5 must be intact for maximal activation of transcription. We also observed that hTRß1 can bind directly to yeast or human GCN5 as well as hADA2, and that the hGCN5_387-837 sequence could bind directly to either GRIP1 or SRC-1 coactivator. Importantly, the T₃-dependent binding of hTRß1to hGCN5_387-837 could be markedly increased by the presence of GRIP1 or SRC1. Mutagenesis of GRIP1 nuclear receptor (NR) Box II and III LXXLL motifs also substantially decreased both in vivo activation of transcription and in vitro T₃-dependent binding of hTRß1 to hGCN5. Taken together, these experiments support a multistep model of transcriptional initiation wherein the binding of T₃ to hTRß1 initiates the recruitment of p160 coactivators and GCN5 to form a trimeric transcriptional complex that activates target genes through interactions with ADA/SAGA adaptor proteins and nucleosomal histones.

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