Subcellular localization of the aryl hydrocarbon receptor is modulated by the immunophilin homolog hepatitis B virus X-associated protein 2

The hepatitis B virus X-associated protein 2 (XAP2) is an immunophilin homo log and core component of the aryl hydrocarbon receptor (AhR). Immunophilin s are components of many steroid receptor complexes, serving a largely unkn own function, Transiently expressed AhR.YFP (yellow fluorescent protein) lo calized to the nuclei of COS-l and NIH-3T3 cells. Go-expression of AhR YFP with XAP2 restored cytoplasmic localization, which was reversed by 2,3,7,8- tetrachlorodibenzo-p-dioxin treatment (TCDD), The effect of XAP2 on AhR loc alization was specific involving a nuclear localization signal-mediated pat hway. Examination of the ratio of AhR to XAP2 in the AhR complex revealed t hat similar to 25% of transiently expressed AhR was associated with XAP2, i n contrast with similar to 100% when the AhR and XAP2 were coexpressed. Str ikingly, TCDD did not influence these ratios, suggesting that ligand bindin g initiates nuclear translocation prior to complex dissociation. Analysis o f endogenous AhR in Hepa-l cells revealed that similar to 40% of the AhR co mplex was associated with XAP2, predicting observed AhR localization to cyt oplasm and nuclei. This study reveals a novel functional role for the immun ophilin-like component of a soluble receptor complex and provides new insig ht into the mechanism of AhR-mediated signal transduction, demonstrating th e existence of two structurally distinct and possibly functionally unique f orms of the AhR.