#NUCLEAR TIME PST SKIN#
These studies revealed important physiological functions in the immune response 8, autoimmunity 9, 10, carcinogenesis 11, apoptosis 12, skin differentiation 13, as well as in endocrine 14, 15 and host-microbiome 16 signalling. Since then, certain endogenous ligands 6, 7 and additional properties of the AHR have been widely explored. Amongst other effects receptor activation induces expression of key enzymes of oxidative phase-I metabolism, notably cytochrome P450-dependent monooxygenases (CYPs) 1A1 and 1B1, both of which convert benzopyrene and other carcinogenic PAHs into highly mutagenic diol-epoxide intermediates 5. Further xenobiotic ligands include β-naphthoflavone (βNF), polychlorinated biphenyls, as well as carcinogenic polycyclic aromatic hydrocarbons (PAHs) 4. Originally identified for its association with xenobiotic ligands, particularly 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) 3, this receptor became quickly recognised as one of the major regulators for eukaryotic phase-I metabolism. The AHR is a highly conserved protein belonging to the basic helix-loop helix (bHLH)-PAS family 1, 2. In concert, these motifs maintain a predominant cytoplasmic compartmentalisation, receptive for ligand binding. Nucleocytoplasmic distribution of full-length human AHR is further affected by a section of the PST domain that shows sequence similarities with nuclear export signals. Nuclear export therefore depends on the previously characterised N-terminal NES and the newly identified motif that includes V647.
Together, this defined region within the Q-rich domain regulates intracellular trafficking of the AHR in context of both nucleocytoplasmic shuttling and receptor activation. Although ligands accelerate nuclear import transiently, stable nuclear transition depends on a motif adjacent to Val 647 that comprises residues 650–661.
Concomitantly mutants lacking this residue are exclusively localised in the nucleus. This residue prevents inactivation of the receptor as a consequence of nuclear sequestration via constitutive import. We have now identified Val 647 as mandatory residue for export from the nucleus and AHR-function. The aryl hydrocarbon receptor (AHR) shuttles continuously between cytoplasm and nucleus, unless ligand-binding triggers association with the AHR nuclear translocator (ARNT) and subsequent binding to cognate DNA motifs.