AhR signal transduction pathway

The Aryl Hydrocarbon Receptor (AhR) is a ligand-activated transcription factor that plays a crucial role in regulating gene expression in response to both environmental and endogenous stimuli, known as ligands. These ligands can include 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD), polycyclic aromatic hydrocarbons (PAHs), or endogenous compounds such as kynurenine, natural plant flavonoids, polyphenols, and indoles, as well as synthetic polycyclic aromatic hydrocarbons and dioxin-like compounds.

Non-ligand bound Aryl Hydrocarbon Receptor (AhR) is retained in the cytoplasm as an inactive protein complex consisting of a

• dimer of Heat shock protein 90 (HSP90)
  Denis et al. 1988 Biochemical and Biophysical Research Communications 155(2): 801-807
  Perdew 1988 The Journal of Biological Chemistry 263(27): 13802-13805)


• Prostaglandin E synthase 3 (PTGES3, p23) as co-chaperone
  Kazlauskas et al. 1999 The Journal of Biological Chemistry 274(19): 13519-13524
  Kazlauskas et al. 2001 Molecular and Cellular Biology 21(7): 2594-2607
  Shetty et al. 2003 Biochemical Pharmacology 65(6): 941-948
  Cox & Miller 2004 Cell Stress & Chaperones 9(1): 4-20


• a single molecule of the immunophilin-like AH receptor-interacting protein, also known as Hepatitis B virus X-associated protein 2 (XAP2)
  Meyer et al. 1998 Molecular and Cellular Biology 18(2): 978-988

Heat shock protein 90 (HSP90) forms a dimer that, together with Prostaglandin E synthase 3 (p23), plays a multifunctional role. It protects the receptor from proteolysis, maintains the receptor in a conformation that is receptive to ligand binding, and prevents the premature binding of Aryl hydrocarbon receptor nuclear translocator (ARNT).
Pongratz et al. 1992 The Journal of Biological Chemistry 267(19): 13728-13734
Whitelaw et al. 1993 Molecular and Cellular Biology 13(4): 2504-2514
Carver et al. 1994 The Journal of Biological Chemistry 269(48): 30109-30112
Coumailleau et al. 1995 The Journal of Biological Chemistry 270(42): 25291-25300
Kazlauskas et al. 1999 The Journal of Biological Chemistry 274(19): 13519-13524
Shetty et al. 2003 Biochemical Pharmacology 65(6): 941-948

When a ligand binds, the chaperones separate, allowing AhR to move into the nucleus where it pairs with Aryl hydrocarbon receptor nuclear translocator (ARNT). This pairing causes alterations in gene transcription. Once activated, AhR exits the nucleus and is broken down by the proteasome, which ensures that its signaling is controlled over time.
Larigot et al. 2018 Biochim Open 7: 1-9
Bahman et al. 2024 Front Immunol 15: 1421346

The AhR/ARNT complex plays a vital role in controlling the expression of genes that are involved in the metabolism of xenobiotics, including CYP1A1, CYP1A2, and CYP1B1. This pathway is essential for detoxification processes. When AhR is activated, it induces the AhR repressor (AhRR), which serves as a negative regulator. The AhRR competes with AhR for binding to ARNT, thereby restricting the gene expression mediated by AhR.
Larigot et al. 2018 Biochim Open 7: 1-9

see also:
Aryl Hydrocarbon Receptor (AhR)
Aryl Hydrocarbon Receptor (AhR) agonists
Aryl Hydrocarbon Receptor (AhR) antagonists
Aryl Hydrocarbon Receptor (AhR) & Biological effects / Functions
Aryl Hydrocarbon Receptor (AhR) & Colitis / Intestinal Inflammation