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

Significance Glucocorticoid receptor (GR) belongs to the nuclear receptor superfamily and functions as a transcription factor. GR regulates various physiological processes, including cell proliferation, energy homeostasis, and inflammation. In this study, we provide molecular evidence for the role of GR in the regulation of mRNA stability, which we term GR-mediated mRNA decay (GMD). Efficient GMD requires a ligand, a GR loaded onto target mRNA, upstream frameshift 1 (UPF1), and proline-rich nuclear receptor coregulatory protein 2. GMD functions in the chemotaxis of human monocytes by targeting chemokine (C-C motif) ligand 2 mRNA. Thus, we unravel a previously unappreciated role of GR, which is traditionally considered a transcription factor, in posttranscriptional regulation. 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.