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

The human pregnane X receptor (hPXR), a major chemical toxin sensor, is a ligand-induced transcription factor activated by various xenobiotics and toxins, resulting in the transcriptional upregulation of detoxifying enzymes. To date, little is known about the upstream regulation of hPXR. Using mass spectrometry analysis and kinome-wide siRNA screen, we report that the E3 ligase UBR5 and DYRK2 regulates 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 a substrate for DYRK2, and DYRK2-dependent phosphorylation on hPXR facilitated its subsequent ubiquitination by UBR5. This is the first report of the posttranslational regulation of hPXR via phosphorylation-facilitated ubiquitination by DYRK2 and UBR5. Our results reveal the role of the ubiquitin-proteasomal pathway in modulating hPXR activity and indicate that pharmacological inhibitors to the ubiquitin-proteasomal pathway that regulates hPXR stability may negatively affect treatment outcome from unintended hPXR-mediated drug-drug interactions.

Source: BJ Signal - January 20, 2014 Category: Biochemistry Authors: S Ong, A N. Goktug, A Elias, J Wu, D Saunders, T Chen Tags: BJ Signal Source Type: research