The F-box-only protein 44 regulates pregnane X receptor protein level by ubiquitination and degradation.
10.1016/j.apsb.2023.07.014
- Author:
Rebecca R FLORKE GEE
1
;
Andrew D HUBER
1
;
Jing WU
1
;
Richa BAJPAI
2
;
Allister J LOUGHRAN
2
;
Shondra M PRUETT-MILLER
2
;
Taosheng CHEN
1
Author Information
1. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
2. Center for Advanced Genome Engineering and Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
- Publication Type:Journal Article
- Keywords:
CYP3A4;
Drug–drug interactions;
E3 ligase;
FBXO44;
Nuclear receptor;
PXR;
Proteasomal degradation;
Ubiquitination
- From:
Acta Pharmaceutica Sinica B
2023;13(11):4523-4534
- CountryChina
- Language:English
-
Abstract:
Pregnane X receptor (PXR) is a ligand-activated nuclear receptor that transcriptionally upregulates drug-metabolizing enzymes [e.g., cytochrome P450 3A4 (CYP3A4)] and transporters. Although the regulation of PXR target genes is well-characterized, less is known about the regulation of PXR protein level. By screening an RNAi library, we identified the F-box-only protein 44 (FBXO44) as a novel E3 ligase for PXR. PXR abundance increases upon knockdown of FBXO44, and, inversely, decreases upon overexpression of FBXO44. Further analysis revealed that FBXO44 interacts with PXR, leading to its ubiquitination and proteasomal degradation, and we determined that the F-box associated domain of FBXO44 and the ligand binding domain of PXR are required for the functional interaction. In summary, FBXO44 regulates PXR protein abundance, which has downstream consequences for CYP3A4 levels and drug-drug interactions. The results of this study provide new insight into the molecular mechanisms that regulate PXR protein level and activity and suggest the importance of considering how modulating E3 ubiquitin ligase activities will affect PXR-mediated drug metabolism.
