Molecular basis of crosstalk in nuclear receptors: heterodimerization between PXR and CAR and the implication in gene regulation.

Abstract

The 48 human nuclear receptors (NRs) form a superfamily of transcription factors that regulate major physiological and pathological processes. Emerging evidence suggests that NR crosstalk can fundamentally change our understanding of NR biology, but detailed molecular mechanisms of crosstalk are lacking. Here, we report the molecular basis of crosstalk between the pregnane X receptor (PXR) and constitutive androstane receptor (CAR), where they form a novel heterodimer, resulting in their mutual inhibition. PXR and CAR regulate drug metabolism and energy metabolism. Although they have been broadly perceived as functionally redundant, a growing number of reports suggests a mutual inhibitory relation, but their precise mode of coordinated action remains unknown. Using methods including RNA sequencing, small-angle X-ray scattering and crosslinking mass spectrometry we demonstrate that the mutual inhibition altered gene expression globally and is attributed to the novel PXR-CAR heterodimerization via the same interface used by each receptor to heterodimerize with its functional partner, retinoid X receptor (RXR). These findings establish an unexpected functional relation between PXR, CAR and RXR, change the perceived functional relation between PXR and CAR, open new perspectives on elucidating their role and designing approaches to regulate them, and highlight the importance to comprehensively investigate nuclear receptor crosstalk.

• Authors: Monicah N Bwayi, Efren Garcia-Maldonado, Sergio C Chai, Boer Xie, Shirish Chodankar, Andrew D Huber, Jing Wu, Kavya Annu, William C Wright, Hyeong-Min Lee, Jayaraman Seetharaman, Jingheng Wang, Cameron D Buchman, Junmin Peng, Taosheng Chen
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 50 Issue 6 Pg. 3254-3275 (04 08 2022) ISSN: 1362-4962 [Electronic] England
• PMID: 35212371 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.

Chemical References

• Constitutive Androstane Receptor
• NR1I2 protein, human
• NR1I3 protein, human
• Pregnane X Receptor
• Receptors, Cytoplasmic and Nuclear

Topics

• Constitutive Androstane Receptor (metabolism)
• Dimerization
• Gene Expression Regulation
• Humans
• Pregnane X Receptor (metabolism)
• Receptors, Cytoplasmic and Nuclear (metabolism)