Alternative effects of the ubiquitin-proteasome pathway on glucocorticoid receptor down-regulation and transactivation are mediated by CHIP, an E3 ligase.
The ubiquitin/proteasome-dependent protein degradation pathway (UPP) is responsible for the accelerated down-regulation of glucocorticoid receptor (GR) levels in cells subjected to chronic glucocorticoid exposure. Whereas hormone-dependent down-regulation of GR operates in most cells, the receptor is not down-regulated after long-term glucocorticoid treatment of either cultured embryonic hippocampal neurons or the HT22 hippocampal cell line. In this report, we show that stable overexpression of the carboxy terminus of heat shock protein 70-interacting protein (CHIP) E3 ligase can restore hormone-dependent down-regulation of GR in HT22 cells. Proteasome inhibitor studies establish that ubiquitylated GR can be efficiently engaged with the proteasome upon CHIP overexpression, unlike the case in parental HT22 cells. In addition to its impact on GR down-regulation, CHIP overexpression alters the coupling between the UPP and GR transactivation. Unlike other steroid receptors whose transactivation properties are typically reduced upon proteasome inhibition, GR transactivation in HT22 cells and other cell lines is enhanced upon proteasome inhibition. However, in HT22 cells overexpressing CHIP, proteasome inhibition leads to a reduction in GR transactivation activity. Thus, the divergent response of a single transactivator (i.e. GR) to the UPP can be dictated by CHIP, an E3 ligase that also functions as a proteasome-targeting factor.
Wang
Xinjia
X
Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
DeFranco
Donald B
DB
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D015536:Down-Regulation; D017930:Genes, Reporter; D005822:Genetic Vectors; D005938:Glucocorticoids / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D017434:Protein Structure, Tertiary; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis*; D013997:Time Factors; D015533:Transcriptional Activation; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
D005938:Glucocorticoids; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011965:Receptors, Glucocorticoid; D025801:Ubiquitin; D008156:Luciferases; C467728:STUB1 protein, human; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex