Abstract
Abstract The orphan hormone receptor RORgt is a transcription factor that is expressed in lymphoid tissue inducer cells, double positive thymocytes, and Th17 cells. Analysis of RORg-deficient mice has revealed that this factor is critical for normal function of all three of these cell types. It is therefore of interest to understand how RORgt function is regulated. We have found that RORgt function can be negatively regulated by Egr3, a zinc finger transcription factor that is induced by a variety of stimuli, including TCR signaling. Ectopic expression of both RORgt and Egr3 in a thymocyte cell line prevents RORgt from binding to target gene promoters, and blocks target gene expression. We have employed multiple strategies to demonstrate that the inhibition of RORgt function is due to direct binding of RORgt by Egr3. Immunoprecipitation of either Egr3 or RORgt brings down the other protein, even when both proteins are obtained by in vitro translation. A mammalian two-hybrid system also indicates that the two proteins physically interact. Mutational analysis of RORgt indicates that the domain responsible for steroid receptor coactivator recruitment is required for binding to Egr3. These studies demonstrate a novel function for Egr3, and suggest a mechanism for regulation of thymocyte and Th17 cell differentiation. This work is funded by a grant from the American Cancer Society.
Published Version
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