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

Bwayi, Monicah N.; Garcia-Maldonado, Efren; Chai, Sergio C.; Xie, Boer; Chodankar, Shirish; Huber, Andrew D.; Wu, Jing; Annu, Kavya; Wright, William C.; Lee, Hyeong-Min; Seetharaman, Jayaraman; Wang, Jingheng; Buchman, Cameron D.; Peng, Junmin; Chen, Taosheng

doi:10.1093/nar/gkac133

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

Journal Article · 24 February 2022 · Nucleic Acids Research

DOI: https://doi.org/10.1093/nar/gkac133 · OSTI ID:2470280

Bwayi, Monicah N. ^[1]; Garcia-Maldonado, Efren ^[1];

^[1]; Xie, Boer ^[1]; Chodankar, Shirish ^[2]; Huber, Andrew D. ^[1]; Wu, Jing ^[1]; Annu, Kavya ^[1]; Wright, William C. ^[1]; Lee, Hyeong-Min ^[1]; Seetharaman, Jayaraman ^[1]; Wang, Jingheng ^[1]; Buchman, Cameron D. ^[1]; Peng, Junmin ^[1];

^[1]

St. Jude Children's Research Hospital, Memphis, TN (United States)
Brookhaven National Laboratory (BNL), Upton, NY (United States). National Synchrotron Light Source II (NSLS-II)

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.

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Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: SC0012704

OSTI ID:: 2470280

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 6 Vol. 50; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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