Xap2
Hsp2
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.
