title: Defining the role for XAP2 in stabilization of the dioxin receptor.
abstract: The dioxin receptor (DR) is a ligand-activated transcription factor that is activated upon binding of dioxins or structurally related forms of xenobiotics. Upon binding ligand the DR translocates from the cytoplasm to the nucleus where it complexes with the partner protein Arnt to form a DNA binding heterodimer, which activates transcription of target genes involved in xenobiotic metabolism. Latency of the DR signaling pathway is maintained by association of the DR with a number of molecular chaperones including the 90-kDa heat shock protein (hsp90), the hepatitis B virus X-associated protein (XAP2), and the 23-kDa heat shock protein (p23). Here we investigated the role of XAP2 in DR signaling and demonstrated that reduced levels of XAP2 labilize the DR, arguing for a function of XAP2 beyond its reported role as a cytoplasmic retention factor. In addition, we showed that a constitutively nuclear DR is degraded in the nucleus and does not require nuclear export for efficient degradation. We also provided evidence implicating the ubiquitin ligase protein C-terminal hsp70-interacting protein (CHIP) in the degradation of the DR, and we demonstrated that this degradation can be overcome by overexpression of XAP2. XAP2 protection of CHIP-mediated degradation is dependent on the tetratricopeptide repeat domain of XAP2 and suggests a mechanism whereby competition for the C-terminal tetratricopeptide repeat acceptor site of hsp90 guides the protein triage decision, the point of determination for either maturation of DR folding or DR degradation.
authors.affiliation: School of Molecular and Biomedical Sciences (Biochemistry) and the Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lees
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Peet
authors.forename: Murray L
authors.initials: ML
authors.lastname: Whitelaw
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D017353:Gene Deletion; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000502:physiology*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008164:Luminescent Proteins; D016376:Oligonucleotides, Antisense; D011506:Proteins; D018336:Receptors, Aryl Hydrocarbon; C103265:aryl hydrocarbon receptor-interacting protein; D049452:Green Fluorescent Proteins; D004247:DNA; D008156:Luciferases; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases