The Landscape of AhR Regulators and Coregulators to Fine-Tune AhR Functions

Abstract

The aryl-hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates numerous cellular responses. Originally investigated in toxicology because of its ability to bind environmental contaminants, AhR has attracted enormous attention in the field of immunology in the last 20 years. In addition, the discovery of endogenous and plant-derived ligands points to AhR also having a crucial role in normal cell physiology. Thus, AhR is emerging as a promiscuous receptor that can mediate either toxic or physiologic effects upon sensing multiple exogenous and endogenous molecules. Within this scenario, several factors appear to contribute to the outcome of gene transcriptional regulation by AhR, including the nature of the ligand as such and its further metabolism by AhR-induced enzymes, the local tissue microenvironment, and the presence of coregulators or specific transcription factors in the cell. Here, we review the current knowledge on the array of transcription factors and coregulators that, by interacting with AhR, tune its transcriptional activity in response to endogenous and exogenous ligands.

Keywords: arylhydrocarbon receptor (AhR); coregulators; immune regulation; nuclear coactivator; transcription factors.

Figure 1

The canonical aryl-hydrocarbon receptor (AhR) pathway. AhR ligands from different sources can cross the plasma membrane and bind to AhR. This allows the translocation of the ligand–receptor complex to the nucleus. In the nucleus, AhR heterodimerizes with its partner ARNT (AhR Nuclear Translocator, also called HIF-1β). The heterodimer binds specific DNA regions located in the promoter of target genes, named dioxin response elements (DRE). AhR-ARNT induces the transcription of target genes, including members of the Cyp1a and Cyp1b families, by the recruitment of various coactivators, such as CBP/p300 (cAMP response element-binding protein) and SRC-1 (steroid receptor coactivator 1). AhRR further suppresses AhR transcriptional activity. Then, after being exported out of the nucleus, AhR is rapidly degraded in the cytoplasmic compartment by the proteasome.

Figure 2

The multiple trajectories regulating immune and nonimmune functions. The modulation of AhR-dependent gene transcription is achieved through the recruitment of specific transcription factors and coregulators, either coactivators (here in red) or corepressors (here in grey). Besides canonical signaling, AhR can directly interact with ER, RB, E2F1, STAT1, NF-κB transcription factors RelA and RelB, leading to the modulation of estrogenic signals, cell cycle progression, apoptosis, and inflammatory responses, respectively. By competing with AhR, HIF1α binds the nuclear translocator ARNT and thus enhances the expression of hypoxia target genes and indirectly suppresses the AhR activity. AhR, by heterodimerizing with the transcriptional activator BMAL1, interferes with the transcription of CLOCK target genes. Specific coactivators (including NCOA family members and PRMT) drive AhR activity directly or indirectly (via CBP and p300) by promoting the transcription of the nuclear translocator ARNT. BMAL1, brain and muscle ARNT-Like 1; CBP, cAMP response element-binding protein (CREB)-binding protein; CLOCK, circadian locomotor output cycles kaput; E6-AP, ubiquitin E3-ligase; E2F1, E2F Transcription Factor 1; ERα, estrogen receptor; HIF1a, hypoxia-inducible factors; NCOA, nuclear receptor coactivators; NCOR, nuclear receptor corepressors; PRMT, protein arginine methyltransferases.