title: Identification and molecular characterization of cellular factors required for glucocorticoid receptor-mediated mRNA decay.
abstract: Glucocorticoid (GC) receptor (GR) has been shown recently to bind a subset of mRNAs and elicit rapid mRNA degradation. However, the molecular details of GR-mediated mRNA decay (GMD) remain unclear. Here, we demonstrate that GMD triggers rapid degradation of target mRNAs in a translation-independent and exon junction complex-independent manner, confirming that GMD is mechanistically distinct from nonsense-mediated mRNA decay (NMD). Efficient GMD requires PNRC2 (proline-rich nuclear receptor coregulatory protein 2) binding, helicase ability, and ATM-mediated phosphorylation of UPF1 (upstream frameshift 1). We also identify two GMD-specific factors: an RNA-binding protein, YBX1 (Y-box-binding protein 1), and an endoribonuclease, HRSP12 (heat-responsive protein 12). In particular, using HRSP12 variants, which are known to disrupt trimerization of HRSP12, we show that HRSP12 plays an essential role in the formation of a functionally active GMD complex. Moreover, we determine the hierarchical recruitment of GMD factors to target mRNAs. Finally, our genome-wide analysis shows that GMD targets a variety of transcripts, implicating roles in a wide range of cellular processes, including immune responses.
authors: Creative Research Initiatives Center for Molecular Biology of Translation, Korea University, Seoul 02841, Republic of Korea.|Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea.
authors: Ok Hyun
authors: OH
authors: Park
authors: Creative Research Initiatives Center for Molecular Biology of Translation, Korea University, Seoul 02841, Republic of Korea.|Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea.
authors: Joori
authors: J
authors: Park
authors: Creative Research Initiatives Center for Molecular Biology of Translation, Korea University, Seoul 02841, Republic of Korea.|Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea.
authors: Mira
authors: M
authors: Yu
authors: Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea.
authors: Hyoung-Tae
authors: HT
authors: An
authors: Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea.
authors: Jesang
authors: J
authors: Ko
authors: Creative Research Initiatives Center for Molecular Biology of Translation, Korea University, Seoul 02841, Republic of Korea.|Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea.
authors: Yoon Ki
authors: YK
authors: Kim
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D002633:Chemotaxis / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009000:Monocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D058105:Polymerization; D020365:RNA Helicases; D020871:RNA Stability / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D051840:Y-Box-Binding Protein 1 / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D006360:Heat-Shock Proteins; C437718:PNRC2 protein, human; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D015534:Trans-Activators; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D012260:Ribonucleases; C490788:RIDA protein, human; D000251:Adenosine Triphosphatases; D020365:RNA Helicases; C101828:UPF1 protein, human
keywords: HRSP12; PNRC2; UPF1; YBX1; glucocorticoid receptor-mediated mRNA decay