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t Recruits Steroid Receptor Coactivators to Ensure Thymocyte Survival
Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, IL 60612
Thymocytes undergo apoptosis unless a functional TCR is assembled. Steroid receptor coactivators (SRCs) regulate nuclear receptor-mediated transcription by associated histone acetyltransferase activity. However, it has been a challenge to demonstrate the in vivo function of SRCs due to the overlapping functions among different members of SRCs. In this study, we show that recruitment of SRCs is required for thymic-specific retinoic acid-related orphan receptor
(ROR
)t-regulated thymocyte survival in vivo. An activation function 2 domain, identified at the carboxyl terminus of ROR
t, is responsible for recruiting SRCs. A mutation in the activation function domain (Y479F) of ROR
t disrupted the interaction with SRCs and abolished ROR
t-mediated trans-activation but not its ability to inhibit transcription. Transgenes encoding the wild-type ROR
t, but not the mutant, restored thymocyte survival in ROR
null mice. Our results thus clearly demonstrate that ROR
t recruits SRCs to impose a gene expression pattern required to expand the life span of thymocytes in vivo, which increases the opportunities for assembling a functional TCR.
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