Glucocorticoid receptor interacts with PNRC2 in a ligand-dependent manner to recruit UPF1 for rapid mRNA degradation

Proceedings of the National Academy of Sciences of the United States of America
Hana ChoYoon Ki Kim

Abstract

Glucocorticoid receptor (GR), which was originally known to function as a nuclear receptor, plays a role in rapid mRNA degradation by acting as an RNA-binding protein. The mechanism by which this process occurs remains unknown. Here, we demonstrate that GR, preloaded onto the 5'UTR of a target mRNA, recruits UPF1 through proline-rich nuclear receptor coregulatory protein 2 (PNRC2) in a ligand-dependent manner, so as to elicit rapid mRNA degradation. We call this process GR-mediated mRNA decay (GMD). Although GMD, nonsense-mediated mRNA decay (NMD), and staufen-mediated mRNA decay (SMD) share upstream frameshift 1 (UPF1) and PNRC2, we find that GMD is mechanistically distinct from NMD and SMD. We also identify de novo cellular GMD substrates using microarray analysis. Intriguingly, GMD functions in the chemotaxis of human monocytes by targeting chemokine (C-C motif) ligand 2 (CCL2) mRNA. Thus, our data provide molecular evidence of a posttranscriptional role of the well-studied nuclear hormone receptor, GR, which is traditionally considered a transcription factor.

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Citations

May 20, 2017·Cellular and Molecular Life Sciences : CMLS·Hoi-Hin KwokRicky Ngok-Shun Wong
Jan 10, 2018·Cold Spring Harbor Perspectives in Biology·Adam M Heck, Jeffrey Wilusz
Apr 29, 2018·Journal of Pharmacokinetics and Pharmacodynamics·Vivaswath S AyyarWilliam J Jusko
Oct 12, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Incheol RyuYoon Ki Kim
Aug 9, 2018·The Journal of Pharmacology and Experimental Therapeutics·Vivaswath S AyyarWilliam J Jusko
Mar 27, 2020·Experimental & Molecular Medicine·Sung Ho Boo, Yoon Ki Kim
Jul 9, 2020·Biomolecules·Daria Lavysh, Gabriele Neu-Yilik
Aug 2, 2018·Clinical Science·Simona RonchettiCarlo Riccardi
Jun 28, 2018·Frontiers in Immunology·Oxana BereshchenkoCarlo Riccardi
Jul 3, 2021·International Journal of Molecular Sciences·Tomoshige KinoJames H Segars
Dec 19, 2017·Chemical Reviews·Xavier RamboutLynne E Maquat

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