Kazlauskas A, Poellinger L, Pongratz I
Department of Cell and Molecular Biology, Karolinska Institute, S-171 77 Stockholm, Sweden.
J Biol Chem. 2000 Dec 29;275(52):41317-24. doi: 10.1074/jbc.M007765200.
The dioxin (aryl hydrocarbon) receptor is a ligand-dependent transcription factor that induces expression of a number of genes encoding drug metabolizing enzymes. The nonactivated form of the dioxin receptor is associated with heat shock protein (hsp) 90, the co-chaperone p23, and the immunophilin-like protein XAP2. Whereas hsp90 has a role in maintenance of the high-affinity ligand binding conformation of the dioxin receptor complex, and p23 stabilizes receptor-hsp90 interaction, the exact role of XAP2 is largely unknown. Here we show that XAP2 protected the ligand-free form of receptor against ubiquitination, resulting in increased dioxin receptor protein levels. Upon exposure to ligand, nuclear translocation of the dioxin receptor was markedly delayed by XAP2, indicating an additional role of XAP2 in regulation of the subcellular localization of the receptor by a mechanism of cytoplasmic retention. In order to mediate these effects, XAP2 required stable association with the hsp90-p23 molecular chaperone complex. The association of XAP2 as well as p23 with the dioxin receptor was determined by the functional state of hsp90. These data indicate a novel mode of regulation of dioxin receptor signaling by the hsp90-dependent molecular chaperone machinery.
二噁英（芳基烃）受体是一种依赖配体的转录因子，可诱导许多编码药物代谢酶的基因表达。二噁英受体的非活化形式与热休克蛋白（hsp）90、共伴侣蛋白p23以及亲免素样蛋白XAP2相关。虽然hsp90在维持二噁英受体复合物的高亲和力配体结合构象中起作用，且p23可稳定受体与hsp90的相互作用，但XAP2的确切作用在很大程度上尚不清楚。在此我们表明，XAP2保护无配体形式的受体不被泛素化，从而导致二噁英受体蛋白水平升高。在接触配体后，XAP2显著延迟了二噁英受体的核转位，表明XAP2通过细胞质滞留机制在调节受体亚细胞定位方面具有额外作用。为介导这些效应，XAP2需要与hsp90 - p23分子伴侣复合物稳定结合。XAP2以及p23与二噁英受体的结合取决于hsp90的功能状态。这些数据表明了hsp90依赖性分子伴侣机制对二噁英受体信号传导的一种新型调节模式。
