Two parallel pathways mediate cytoplasmic localization of the dioxin (aryl hydrocarbon) receptor.
The dioxin receptor is a ligand-dependent transcription factor that mediates the biological effects of dioxin and related environmental pollutants. In the absence of ligand the receptor is present in the cytoplasmic compartment of the cell associated with the hsp90-dependent chaperone complex. This complex regulates several functions of the receptor such as ligand binding and nuclear import. Furthermore, intracellular localization of the receptor is modulated by multiple factors such as the export protein CRM-1 and the hsp90-associated immunophilin XAP-2. We have identified the mechanism of XAP-2-induced cytoplasmic localization of the receptor and studied the potential cross-talk between CRM-1 and XAP-2. We show that XAP-2 anchors the ligand-free receptor to cytoskeletal structures. This effect is blocked upon treatment with the actin inhibitor cytochalasin B, whereas the tubulin inhibitor colchicine had no effect on receptor localization. In addition, we show that the receptor interacts with CRM-1 both in the presence and absence of ligand. CRM-1-mediated nuclear export occurs independently of XAP-2. Our data provide evidence that CRM-1 and XAP-2 act in parallel through different mechanisms and target different interfaces of the receptor. These results suggest that two pathways cooperate to localize the non-activated receptor in the cytoplasmic compartment of the cell.
Berg
Petra
P
Department of Cell and Molecular Biology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Pongratz
Ingemar
I
D003078:Colchicine / Q000494:pharmacology; D003571:Cytochalasin B / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D028884:Karyopherins / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000097606:Exportin 1 Protein
D003078:Colchicine; D003571:Cytochalasin B; D049452:Green Fluorescent Proteins; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D028884:Karyopherins; D008164:Luminescent Proteins; D018832:Molecular Chaperones; D000072317:Polychlorinated Dibenzodioxins; D011506:Proteins; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D000097606:Exportin 1 Protein; C103265:aryl hydrocarbon receptor-interacting protein