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 hypothalamo-hypophyseal-thyroid axis and hence thyroid hormone (triiodothyronine (T(3))) homeostasis. The two beta thyroid hormone receptors, TRbeta1 and TRbeta2, contribute to T(3) feedback on TRH, with TRbeta1 having a more important role in the activation of TRH transcription. How TRbeta1 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 TRbeta1, 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 TRbeta1, and were enhanced by T(3) both in yeast and mammalian cells. Furthermore, small inhibitory RNA-mediated knockdown of XAP2 in vitro affected the stability of TRbeta1. In vivo, siXAP2 abrogated specifically TRbeta1-mediated (but not TRbeta2) activation of hypothalamic TRH transcription. This study provides the first in vivo demonstration of a regulatory, physiological role for XAP2.
Froidevaux
Marie-Stéphanie Clerget
MS
UMR 5166, CNRS/MNHN USM 501, 57 rue Cuvier, Bp 32, Paris Cedex 05, France.
Berg
Petra
P
Seugnet
Isabelle
I
Decherf
Stéphanie
S
Becker
Nathalie
N
Sachs
Laurent M
LM
Bilesimo
Patrice
P
Nygård
Maria
M
Pongratz
Ingemar
I
Demeneix
Barbara A
BA
D000818:Animals; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism* / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism*; D014018:Tissue Distribution; D015533:Transcriptional Activation; D014162:Transfection
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D037042:Thyroid Hormone Receptors beta; C103265:aryl hydrocarbon receptor-interacting protein; D013973:Thyrotropin-Releasing Hormone