The immunophilin-like protein XAP2 regulates ubiquitination and subcellular localization of the dioxin receptor.
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.
Kazlauskas
A
A
Department of Cell and Molecular Biology, Karolinska Institute, S-171 77 Stockholm, Sweden.
Poellinger
L
L
Pongratz
I
I
D000818:Animals; D016227:Benzoquinones; D019556:COS Cells; D003593:Cytoplasm / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D047029:Lactams, Macrocyclic; D011506:Proteins / Q000502:physiology*; D011809:Quinones / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000032:analysis* / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism*
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047029:Lactams, Macrocyclic; D011506:Proteins; D011809:Quinones; D018336:Receptors, Aryl Hydrocarbon; D014452:Ubiquitins; C103265:aryl hydrocarbon receptor-interacting protein; C001277:geldanamycin