Regulation of subnuclear localization is associated with a mechanism for nuclear receptor corepression by RIP140.
Regulation of gene transcription by nuclear receptors involves association with numerous coregulators. Receptor-interacting protein 140 (RIP140) is a corepressor that negatively regulates the ligand-induced activity of several nuclear receptors, including the glucocorticoid receptor (GR). In the present study, we have characterized the role of the intranuclear localization of RIP140 in its corepressor activity. In the absence of ligand-activated GR, RIP140 is localized in small nuclear foci targeted by a 40-amino-acid-long sequence. Although the focus-targeting domain overlaps with a binding sequence for the corepressor CtBP (C-terminal binding protein), interaction with CtBP is not involved in the localization. RIP140 foci do not correspond to PML bodies but partly colocalize with domains harboring the corepressor SMRT. Upon ligand binding, GR and RIP140 are redistributed to large nuclear domains distinct from the RIP140 foci. The redistribution requires regions of RIP140 with corepressor activity, as well as the DNA-binding domain of GR. Furthermore, we show that full RIP140 corepressor activity is contributed both by C-terminal receptor-binding LXXLL motifs and interaction with the CtBP corepressor. In conclusion, our results suggest that the corepressor function of RIP140 is multifaceted and involves binding to nuclear receptors, as well as additional functions mediated by the formation and intranuclear relocalization of a repressive protein complex.
Tazawa
Hiroshi
H
Departments of Medical Nutrition. Biosciences, Karolinska Institutet, Novum, S-141 86 Huddinge, Sweden.
Osman
Waffa
W
Shoji
Yutaka
Y
Treuter
Eckardt
E
Gustafsson
Jan-Ake
JA
Zilliacus
Johanna
J
D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism*; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008164:Luminescent Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000378:metabolism*; D000078723:Nuclear Receptor Interacting Protein 1; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D008024:Ligands; D008164:Luminescent Proteins; C000627127:NRIP1 protein, human; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D005982:Glutathione Transferase