The co-chaperone XAP2 is required for activation of hypothalamic thyrotropin-releasing hormone transcription in vivo

Transcriptional control of hypothalamic thyrotropin-releasing hormone (TRH) integrates central regulation of the hypothalamohypophyseal-thyroid axis and hence thyroid hormone ( triiodothyronine (T-3) homeostasis. The two beta thyroid hormone receptors, TR beta 1 and TR beta 2, contribute to T-3 feedback on TRH, with TRb1 having a more important role in the activation of TRH transcription. How TRb1 fulfils its role in activating TRH gene transcription is unknown. By using a yeast two-hybrid screening of a mouse hypothalamic complementary DNA library, we identified a novel partner for TRb1, hepatitis virus B X-associated protein 2 (XAP2), a protein first identified as a co-chaperone protein. TR-XAP2 interactions were TR isoform specific, being observed only with TR beta 1, and were enhanced by T3 both in yeast and mammalian cells. Furthermore, small inhibitory RNA-mediated knockdown of XAP2 in vitro affected the stability of TR beta 1. In vivo, siXAP2 abrogated specifically TR beta 1-mediated (but not TR beta 2) activation of hypothalamic TRH transcription. This study provides the first in vivo demonstration of a regulatory, physiological role for XAP2.