AHR/ARNT
Transcription Factors

DEFINITION

The aryl hydrocarbon receptor is a member of the family of basic helix-loop-helix transcription factors. AHR binds several exogenous ligands such as natural plant flavonoids, polyphenolics, indoles, tetrapyroles and arachidonic acid metabolite as well as synthetic polycyclic aromatic hydrocarbons and dioxin-like compounds. AhR is a cytosolic transcription factor that is normally inactive, bound to several co-chaperones. Upon ligand binding to chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the chaperones dissociate resulting in AhR translocating into the nucleus and dimerizing with ARNT, the AhR nuclear translocator, , also know as HIF-1 beta, leading to changes in gene transcription.

THE GENE

The AhR gene location is 7p15 and it sizes about 47 kbp

CHEMICAL STRUCTURE AND IMAGES

The AhR protein contains several domains critical for function and is classified as a member of the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) family of transcription factors.The bHLH motif is located in the N-terminal of the protein and is a common entity in a variety of transcription factors. Members of the bHLH superfamily have two functionally distinctive and highly conserved domains. The first is the basic-region (b), which is involved in the binding of the transcription factor to DNA. The second is the helix-loop-helix (HLH) region, which facilitates protein-protein interactions. Also contained with the AhR are two PAS domains, PAS-A and PAS-B, which are stretches of 200-350amino acids contained also in AhR’s dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT). The PAS domains support specific secondary interactions with other PAS domain containing proteins, as is the case with AhR and ARNT, so that heterozygous and homozygous protein complexes can form. The ligand binding site of AhR is contained within the PAS-B domain and contains several conserved residues critical for ligand binding. Finally, a Q-rich domain is located in the C-terminal region of the protein and is involved in co-activator recruitment and transactivation.

Wikipedia, AhR: Protein Functional Domains
RCBS Protein Data Bank
Nextprot

AA percentage of AhR, ARNT, XAP2, HSP90

CELLULAR FUNCTIONS

CYP450 INDUCTION

The molecular mechanism governing he inducible exression of CYPs have been successfully elucidated, including the inducers, cis-acting DNA elements, cognate transcription factors and coactivators. The inducible expression of CYP1 family is regulated by a heterodimer of AhR and ARNT

Molecular mechanism of AhR functions in the regulation of cytochrome P450 genes, 2005

E3 UBIQUITIN LIGASE FUNCTION AND MODULATION OF STEROID RECEPTOR

It is well known that AhR ligands negatively or positively regulate the estrogen receptor and androgen receptor activity. The loss of the transactivation potential of ER and AR in the presence of TCDD is reportedly due to a sharp decrease in its ability to bind to DNA responsive element. AhR ligand-induced degradation and functional repression of sex steroid hormone receptors were attenuated by treating with the proteasome inhibitor, MG-132, resulting in polyubiquitylation of the ER, as determined by polyacrylamide gel electrophoresis. Consistent with this observation, we revealed that polyubiquitylation of ERα, AR and even AhR was promoted by AhR ligands in AhR immunoprecipitated complexes, when ubiquitin E1 and E2 ligases were supplemented in vitro.

Molecular mechanisms of the physiological functions of the aryl hydrocarbon (dioxin) receptor, a multifunctional regulator that senses and responds to environmental stimuli, 2010
AhR acts as an E3 ubiquitin ligase to modulate steroid receptor functions, 2009

REPRODUCTION

It is possible that AhR and AhRR regulate the ovarian biological clock by governing the estrous cycle: in fact P450 aromatase (CYP19) expression was not enhanced in the proestrous stage in AhR-deficient mice, leading to markedly reduced ovarian estradiol concentrations compared to wild-type mice. Furthermore several lines of evidence indicate that AhR plays physiological roles in reproduction beyond the estrous cycle.

Molecular mechanisms of the physiological functions of the aryl hydrocarbon (dioxin) receptor, a multifunctional regulator that senses and responds to environmental stimuli, 2010

IMMUNITY AND HEMATOPOYESIS

T CELLS
AhR activation by its high-affinity ligand TCDD in vivo results in the expansion of the CD4+ CD25+ Foxp3+ Treg-cell compartment. These CD4+ CD25+ Foxp3+ Treg cells are functional and suppress the development of experimental autoimmune encephalomyelitis (EAE), experimental autoimmune uveoretinitis, colitis and spontaneous autoimmune diabetes.
Furthermore in vivo, AhR is required for the differentiation of suppressive TR1 cells capable of halting inflammation in experimental models of multiple sclerosis and lupus. Moreover, we also found that AhR was important for the differentiation of human Tr1 cells. Hence, AhR signalling can modulate the differentiation of murine and human IL-10-producing Tr1 cells.
AhR expression is also up-regulated in Th17 cells and AhR ligands can boost the differentiation of Th17 cells. The activation of AhR in vivo by its ligand FICZ boosts the Th17 response and worsens central nervous system autoimmunity.
However this Treg expansion reduces the other T cells population size.

The aryl hydrocarbon receptor: a molecular pathway for the environmental control of the immune response , 2013
The Evolving Role of the Aryl Hydrocarbon Receptor (AhR) in the Normophysiology of Hematopoiesis, 2012

B CELLS
The AhR agonist 2-(1'H-indole-3'- carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), which is derived via tryptophan metabolism, suppressed the expression of not only IgM, but also IgG1 and IgE. ITE was also found to suppress the expression of secreted-type Ig mRNAs and plasma cell-specific genes. These findings indicate that the endogenous AhR agonist suppresses B cell differentiation into Ig-secreting plasma cells.

Effects of AhR ligands on the production of immunoglobulins in purified mouse B cells, 2012

HEMATOPOYESIS
AhR impacts many stages and lineages of hematopoyesis. During the early stages of hematopoiesis, AhR impacts HSCs expansion and pluripotency via regulation of Hif-1α, Oct4, and Notch signaling and although still unproven, AhR could influence megakaryocytic polyploidization and platelet function by many molecular mechanisms

The Evolving Role of the Aryl Hydrocarbon Receptor (AhR) in the Normophysiology of Hematopoiesis, 2012

EMBRYOGENESIS

There are many evidences that suggest that acute exposure to TCDD, an Ahr agonist, has direct effects on early development and directly confirm the importance of Ahr in the processes of embryogenesis

The aryl hydrocarbon receptor agonist 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) alters early embryonic development in a rat IVF exposure model, 2011

CARCINOGENESIS

AhR-dependent enzyme induction increased the frequency of DNA adducts in the lung in AhR-responsive mice. One study suggested that AhR activation and CYP1A1 induction is required for DNA adduct formation and increased apoptotic activity in human lung cells.
Moreover both a direct AhR agonist and overexpression of AhR stimulate cell proliferation by affecting the cell cycle and evidence suggests that AhR mediates deregulation of cell-cell contact by stimulating migration and epithelial mesenchymal transformation.

Aryl Hydrocarbon Receptor and Lung Cancer, 2013

CROSS-TALKING WITH HIPOXIA INDUCIBLE FACTOR 1 (HIF-1)

Most if not all of the toxic responses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are mediated through the AhR, which requires ARNT to regulate gene expression. ARNT is also required by HIF-1alpha to enhance the expression of various genes in response to hypoxia. Since both the AhR and hypoxia transcriptional pathways require ARNT, some of the effects of TCDD and similar types of ligands could be explained by interaction between the AhR and hypoxia pathways involving ARNT.
TCDD significantly reduced the hypoxia-mediated reporter gene activity in B-1 cells. Reciprocally, the hypoxia response inducers desferrioxamine or CoCl(2) inhibited AhR-mediated CYP1A1 enzyme activity and this mutual repression may provide an underlying mechanism for many TCDD-induced toxic responses.

Interactions between aryl hydrocarbon receptor (AhR) and hypoxia signaling pathways, 2001

REGULATION

LIGANDS

XENOBIOTICS
Among the xenobiotic are included some of the most potent activators of Ahr like halogenated-dioxins and related compounds (for example TCDD), polichlorinated biphenyls, polycyclic aromatic hidrocarbons and benzimidazoles (but it still unknown whether the activation is induced by some of their metabolites or ligand-indipendent).

DIETARY
The greatest source of exposure of animals and humans to AhR ligands comes from the diet. Numerous studies have described and characterized a variety of naturally occurring dietary chemicals that can directly activate the AhR signaling pathway, such as extracts of vegetables or vegetable-derived materials (curcumin and carotinoids), flavonoids and indole-3-carbinol derivates.

ENDOGENOUS
A variety of endogenous chemicals have been identified that can bind to the AhR and/or active AhR-dependent gene expression in vitro; however till now none of these seems to have a physiological role, because the concentrations needed to activate the pathway are hardly reached in vivo. These endogenous activators represent several structurally distinct classes of chemical such as indigoids, heme metabolites, 2-(1’H-indole-3’-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), tryptophan metabolites, indoles, ultraviolet photoproducts of tryptophan and arachidonic acid metabolites.

Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals, 2003
The Search for Endogenous Activators of the Aryl Hydrocarbon Receptor, 2009

ARYL HIDROCARBON RECEPTOR REPRESSOR (AHRR)

The classical analysis of AhR function by stimulation with well-characterized xenobiotics has led to a central paradigm in which xenobiotic-mediated AhR activation results in AhR-mediated transcriptional up-regulation of AhRR, the protein product of which feeds back to limit AhR activity with a mechanism of competitive binding to ARNT, competitive binding of ARNT/AhRR dimers to AhREs , and recruitment of co-repressors. However, recent studies demonstrating that AhRR mutants incapable of binding AhREs still suppress AhR activity, even in the presence of excess ARNT , suggest that, as is often the case, mechanisms are more complex than initially appreciated. Furthermore, studies demonstrating AhRR-mediated inhibition of HIF-1 signaling and physical association of the AhRR with the ER encourage caution in ascribing all AhRR activity to its propensity to block AhR activity.

Regulation of Constitutive and Inducible AhR Signaling: Complex Interactions Involving the AhR Repressor, 2009