Molecular mechanisms of the physiological functions of the aryl hydrocarbon (dioxin) receptor, a multifunctional regulator that senses and responds to environmental stimuli

Abstract

The aryl hydrocarbon receptor (AhR) was originally identified as a ligand-activated transcription factor that is involved in the induction of xenobiotic-metabolizing Cytochrome P4501A1 (CYP1A1). For several decades, AhR has been studied in relation to toxicology and pharmacology. With recent discoveries on novel AhR functions, AhR research has expanded into multiple aspects of physiology, such as reproduction, innate immunity and tumor suppression. In this review, we summarize and discuss recent progress in mechanistic and functional studies on AhR with particular emphasis on physiological processes.

Fig. 1

A, A schematic model for the transcriptional regulation of the AhR/Arnt activator complex and the AhRR/Arnt repressor complex. Unmodified Arnt forms a heterodimer with AhR and recruits coactivators, such as CBP/p300, to form the transcriptional activator complex. Meanwhile, Arnt forms a heterodimer with AhRR, which significantly enhances the SUMOylation of both proteins. SUMOylated AhRR recruits corepressors ANKRA2, HDAC4, and HDAC5 to form the transcriptional repressor complex. B, A schematic representation of the full-length 701-amino acid mouse AhRR. The characterized domains represented are the basic helix-loop-helix (bHLH), Per-Arnt-Sim (PAS), and repression domain. Three putative SUMOylation sites are located within the repression domain, with the target lysine residues indicated. XRE: Xenobiotic Responsive Element; BTE: Basic Transcription Element; a GC box sequence

Fig. 2

A schematic model of the AhR- and APC-dependent β-catenin degradation pathways. Ligand-activated AhR translocates into the nucleus where it forms a ubiquitylation complex containing CUL4B and Arnt, whereas the APC-dependent-pathway functions in the cytoplasm. This function of AhR is activated by both xenobiotics and natural AhR ligands, such as indole derivatives (IAA, I3C, DIM. etc.) that are converted from dietary tryptophan and glucosinolates by intestinal microbes.