Fig. 5

AhR signaling pathway. Before ligand binding, AhR remains stable in the cytoplasm within the HSP90/XAP2/p23 complex. When exposed to AhR ligands, such as uremic toxins, pollutants or natural plants, AhR changes its conformation, thus exposing the nuclear localization sequence in its N-terminal region and triggering translocation to the nucleus. In the nucleus, AhR is released from this complex and activated. Activated AhR binds to ARNT and some coactivators to regulate the transcription of target genes containing consensus XRE (xenobiotic response element), such as Cyp1a1, Cyp1a2, AhRR, Nlrp3, IL-10 and IL-22. In addition, AhR regulates the transcription of target genes that do not harbor the canonical XRE recognition site in their promoter regions by interacting with additional transcription factors, such as ER, KLF6, NF-κB and c-Maf. Furthermore, AhR directly regulates the transcription of Nrf2. Additionally, AhR, together with DDB1, Rbx1, TBL3, ARNT and CUL4B, assembles into the novel CUL4B ubiquitin ligase complex CUL4B^AhR to regulate target proteins for ubiquitin degradation, such as ER-α, AR, β-catenin and PPARγ. Ligand-activated cytoplasmic AhR can act as a protein adaptor that links SRC to JAK2, activating the PI3K/AKT, MEK/ERK and YAP/ERK signaling pathways. AhR can also protect tissue factor (TF) from ubiquitination and degradation