Mechanisms of xenobiotic receptor activation: Direct vs. indirect

Abstract

The so-called xenobiotic receptors (XRs) have functionally evolved into cellular sensors for both endogenous and exogenous stimuli by regulating the transcription of genes encoding drug-metabolizing enzymes and transporters, as well as those involving energy homeostasis, cell proliferation, and/or immune responses. Unlike prototypical steroid hormone receptors, XRs are activated through both direct ligand-binding and ligand-independent (indirect) mechanisms by a plethora of structurally unrelated chemicals. This review covers research literature that discusses direct vs. indirect activation of XRs. A particular focus is centered on the signaling control of the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), and the aryl hydrocarbon receptor (AhR). We expect that this review will shed light on both the common and distinct mechanisms associated with activation of these three XRs. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

Keywords: Activation mechanism; AhR; CAR; PXR; Xenobiotic receptor.

Figure 1. Schematic Illustration of Mechanisms of CAR Activation

Direct Activation – CAR is sequestered in a cytoplasmic complex containing HSP90 and CCRP. Upon ligand binding, these chaperones dissociate and CAR translocates to the nucleus where it heterodimerizes with RXR, recruits coactivators GRIP1 and SRC1, and binds to its response element to initiate gene transcription. Indirect Activation – When sequestered in the cytoplasm, the Thr38 residue of CAR is phosphorylated by PKC, and dephosphorylation of this residue for CAR activation can be inhibited by ERK1/2 upon activation of the EGFR signaling pathway. When a PB-like compound binds to the EGFR receptor and inhibits EGF-mediated signaling, RACK1 is dephosphorylated at Tyr52 and recruits PP2A to the CAR protein complex, where it dephosphorylates the Thr38 residue and induces CAR nuclear translocation and activation.

Figure 2. Schematic illustration of Mechanisms of PXR Activation

Direct Activation – PXR is retained in a cytoplasmic complex with HSP90 and CCRP, which dissociate upon ligand binding leading to PXR nuclear accumulation. Unbound PXR in the nucleus is complexed to corepressors NcoR and SMRT, which dissociate upon ligand stimulation, leading to the recruitment of coactivators SRC1 and GRIP1 and the transcription of target genes. Indirect Activation – This is a less well-developed mechanism of PXR activation, although the Ser350, Thr248, Thr290, and Thr408 phosphorylation sites of PXR are known to affect its activation. Compounds disturbing signaling pathways may influence the phosphorylation, nuclear translocation, and target gene express of PXR.

Figure 3. Schematic Illustration of Mechanisms of AhR Activation

Direct Activation – AhR is sequestered in the cytoplasm complexed with HSP90, XAP2, and p23. Ligand binding induces the dissociation of XAP2 and p23 from AhR and the AhR:HSP90 complex translocates to the nucleus. In the nucleus, HSP90 dissociates and AhR heterodimerizes with ARNT to induce transcription of target genes. Indirect Activation – Drugs such as omeprazole and sunitinib translocate and activate AhR by affecting the c-src-dependent and tyrosine kinases (TK)-mediated signaling pathways, respectively. cAMP activates AhR and induces a structural change that translocates AhR to the nucleus and favors ligand-independent protein-protein interaction but not AhR:ARNT heterodimerization.