The role of DNA-binding and ARNT dimerization on the nucleo-cytoplasmic translocation of the aryl hydrocarbon receptor

Abstract

The human aryl hydrocarbon receptor (AHR) is predominantly located in the cytoplasm, while activation depends on its nuclear translocation. Binding to endogenous or xenobiotic ligands terminates the basal nucleo-cytoplasmic shuttling and stabilizes an exclusive nuclear population. The precise mechanisms that facilitate such stable nuclear accumulation remain to be clarified as essential step in the activation cascade. In this study, we have tested whether the sustained nuclear compartmentalization of ligand-bound or basal AHR might further require heterodimerization with the AHR-nuclear translocator (ARNT) and binding to the cognate XRE-motif. Mutagenesis of the DNA-binding motif or of selected individual residues in the ARNT-binding motif did not lead to any variation in AHR’s nucleo-cytoplasmic distribution. In response to ligands, all mutants were retained in the nucleus demonstrating that the stable compartmentalization of activated AHR in the nucleus is neither dependent on interactions with DNA, nor ARNT. Knocking down the ARNT gene using small interfering RNA confirmed that ARNT does not play any role in the intracellular trafficking of AHR.

Molecular Docking Study of Flavonoids to Block the Aryl Hydrocarbon Receptor

“…The activation of AHR is associated with an increase of the oxidative metabolism, and consequently, with the formation of, for instance, reactive oxygen species. Hence, this interaction with DNA in XRE is highly associated with the onset of further toxicity events that include carcinogenicity due to a prolonged AHR activity, development and reproductive toxicity, and immunological deterioration, known as dioxin toxicity effects [1,6,7,[14][15][16][17][18][19][20][21][22].…”

Aromatic oil from lavender as an atopic dermatitis suppressant

“…AhR is a ligand-dependent transcription factor that normally complexes with heat shock protein 90 (Hsp90), hepatitis B virus X-associated protein [XAP2; also known as aryl hydrocarbon receptor-interacting protein (AIP)], and p23. It is localized in the cytoplasm [23], but when it binds to ligands such as air pollutants including dioxins, it translocates into the nucleus. In the nucleus, AhR dissociates from Hsp90, XAP2, and p23 to form a dimer with AhR hydrocarbon receptor nuclear translocator (ARNT).…”