AHR gene

The AHR gene (AHR stands for " Aryl Hydrocarbon Receptor") is a protein-coding gene located on chromosome 7p21.1.

The protein encoded by this gene, an aryl hydrocarbon receptor (AHR), is a cytosolic transcription factor involved in the regulation of biological responses to aromatic hydrocarbons.

The aryl hydrocarbon receptor (AhR) is present in non-active form in the cytosol in a complex with other proteins (hsp90, AIP, p23). Before binding to its ligand, the encoded protein is sequestered in the cytoplasm; after binding to the ligand, this complexed protein migrates into the cell nucleus. There, the Ah receptor forms a dimer with the protein ARNT (Ah receptor nuclear translocator - see ARNT gene below). This complex can bind to certain short DNA sequences in gene promoters. This triggers the transcription of the relevant gene. Among other things, it has been shown that this receptor regulates enzymes that metabolize xenobiotics, such as cytochrome P450 (Ema M et al. 1994).

In principle, it is a ligand-activated transcription factor that enables cells to adapt to changing conditions by sensing compounds from the environment, diet, microbiome and cell metabolism, and plays an important role in development, immunity and tumor entities (MacPherson L et al. 2013; Ema M et al. 1994).

Furthermore, the transcription factor regulates a variety of biological processes, including angiogenesis, hematopoiesis, drug and lipid metabolism, cell motility and immunomodulation. Xenobiotics can act as ligands: When xenobiotics are bound, the expression of several genes for enzymes that metabolize phase I and II chemical xenobiotics (e.g. the CYP1A1 gene) is activated. In addition to xenobiotics, natural ligands derived from plants, microbiota and endogenous metabolism are potent AHR agonists. Tryptophan (Trp) derivatives represent an important class of endogenous AHR ligands (Sadik A et al. 2020).

Acts as a negative regulator of anti-tumor immunity: indoles and kynurenic acid produced by Trp catabolism act as ligands and activate AHR, promoting AHR-driven motility of cancer cells and suppressing adaptive immunity ((Sadik A et al. 2020). Regulates the circadian clock by inhibiting basal and circadian expression of the circadian core component PER1. Inhibits PER1 by suppressing transcriptional activation of PER1 mediated by the CLOCK-BMAL1 heterodimer. The heterodimer ARNT:AHR binds to the DNA core sequence 5'-TGCGTG-3' within the dioxin response element (DRE) of the target gene promoters and activates their transcription (Schulte KW et al. 2017).
It has been shown that the AHR receptor regulates xenobiotic-metabolizing enzymes (xenobiotics = chemical substances that are not naturally formed but are synthesized by humans and are foreign to the biological cycle) such as cytochrome P450.

The AHR functional axis is important for the maintenance of immune tolerance and the development of certain immune subsets, emphasizing the potential role of AHR in PD-1 immunobiology. Understanding the functions of AHR ligands as well as the interaction of AHR with STAT1, NF-κB and EBV may provide insights into disease development, the PD-1 axis and immunotherapies targeting PD-1 and its ligand PD-L1 .

Diseases associated with AHR include:

retinitis pigmentosa

and

Foveal hypoplasia

The AHR protein enables cells to adapt to changing conditions by recognizing compounds from the environment, diet, microbiome, and cell metabolism, and which plays an important role in development, immunity, and cancer (MacPherson L et al. 2013).

AHR is traditionally considered a ligand-activated receptor and transcription factor responsible for the induction of enzymes that metabolize drugs. Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons (Puga A et al. (2002).

The AHR receptor encoded AHR protein regulates a variety of biological processes, including angiogenesis, hematopoiesis, drug and lipid metabolism, cell motility, and immune modulation (Puga A et al. 2002).

Apparently, AHR receptors play a major role in UV-induced pigmentation. Thus, these receptors are produced by all cells of the epidermis (keratinocytes, Langerhans cells, melanocytes). In the skin, AhR functions, among other things, as a sensor that recognizes chemical environmental stimuli. Its importance in dermatological research is increasing now that it is known that AHR performs other diverse tasks in the skin, such as in the aging process or in the homeostasis of immune cells.

1. Ema M et al. (1994) Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors. J Biol Chem 269:27337-2743
2. Gomez A et al. (2018) Characterization of TCDD-inducible poly-ADP-ribose polymerase (TIPARP/ARTD14) catalytic activity. Biochem J 475:3827-3846.
3. MacPherson L et al. (2013) 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase (TiPARP, ARTD14) is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation. Nucleic Acids Res 41:1604-1621.
4. MacPherson L et al. (2013) 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase (TiPARP, ARTD14) is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation. Nucleic Acids Res 41:1604-1621.
5. Puga A et al. (2002). Role of the aryl hydrocarbon receptor in cell cycle regulation. Chem Biol Interact 141:117-130.
6. Sadik A et al. (2020) IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression. Cell 182:1252-1270.
7. Schulte KW et al. (2017) Structural Basis for Aryl Hydrocarbon Receptor-Mediated Gene Activation. Structure 25:1025-1033