Publications

Publication Search

Search for publications by

Stability of the human pregnane X receptor is regulated by E3 ligase UBR5 and serine/threonine kinase DYRK2

Abstract

The hPXR (human pregnane X receptor), a major chemical toxin sensor, is a ligand-induced transcription factor activated by various xenobiotics and toxins, resulting in the transcriptional up-regulation of detoxifying enzymes. To date, little is known about the upstream regulation of hPXR. Using MS analysis and a kinome-wide siRNA screen, we report that the E3 ligase UBR5 (ubiquitin protein ligase E3 component n-recognin 5) and DYRK2 (dual-specificity tyrosine-phosphorylation-regulated kinase 2) regulate hPXR stability. UBR5 knockdown resulted in accumulation of cellular hPXR and a concomitant increase in hPXR activity, whereas the rescue of UBR5 knockdown decreased the cellular hPXR level and activity. Importantly, UBR5 exerted its effect in concert with the serine/threonine kinase DYRK2, as the knockdown of DYRK2 phenocopied UBR5 knockdown. hPXR was shown to be a substrate for DYRK2, and DYRK2-dependent phosphorylation of hPXR facilitated its subsequent ubiquitination by UBR5. This is the first report of the post-translational regulation of hPXR via phosphorylation-facilitated ubiquitination by DYRK2 and UBR5. The results of the present study reveal the role of the ubiquitin-proteasomal pathway in modulating hPXR activity and indicate that pharmacological inhibitors of the ubiquitin-proteasomal pathway that regulate hPXR stability may negatively affect treatment outcome from unintended hPXR-mediated drug-drug interactions.

Type Journal
ISBN 1470-8728 (Electronic) 0264-6021 (Linking)
Authors Ong, S. S.; Goktug, A. N.; Elias, A.; Wu, J.; Saunders, D.; Chen, T.;
Garvan Authors Dr Jianmin Wu
Publisher Name BIOCHEM J
Published Date 2014-01-01 00:00:00
Published Volume 459
Published Issue 1
Published Pages 193-203
URL http://www.ncbi.nlm.nih.gov/pubmed/24438055
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?12414_12772/4590193.pdf