RORgammat recruits steroid receptor coactivators to ensure thymocyte survival.
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 gamma (RORgamma)t-regulated thymocyte survival in vivo. An activation function 2 domain, identified at the carboxyl terminus of RORgammat, is responsible for recruiting SRCs. A mutation in the activation function domain (Y479F) of RORgammat disrupted the interaction with SRCs and abolished RORgammat-mediated trans-activation but not its ability to inhibit transcription. Transgenes encoding the wild-type RORgammat, but not the mutant, restored thymocyte survival in RORgamma null mice. Our results thus clearly demonstrate that RORgammat 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.
Xie
Huimin
H
Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, IL 60612, USA.
Sadim
Maureen S
MS
Sun
Zuoming
Z
D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D002470:Cell Survival; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011987:Receptors, Steroid / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D011948:Receptors, Antigen, T-Cell; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse; D014157:Transcription Factors