Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activator NRF2

NRF2 (nuclear factor erythroid 2-related factor 2) is a key transcriptional activator that mediates the inducible expression of antioxidant genes. NRF2 is normally ubiquitinated by KEAP1 (Kelch-like ECH-associated protein 1) and subsequently degraded by proteasomes. Inactivation of KEAP1 by oxidativ...

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Bibliographic Details
Published in:The Journal of biological chemistry 2017-05, Vol.292 (18), p.7519-7530
Main Authors: Alam, Md. Morshedul, Okazaki, Keito, Nguyen, Linh Thi Thao, Ota, Nao, Kitamura, Hiroshi, Murakami, Shohei, Shima, Hiroki, Igarashi, Kazuhiko, Sekine, Hiroki, Motohashi, Hozumi
Format: Article
Language:English
Subjects:
Acetylation - drug effects
Animals
Dexamethasone - pharmacology
electrophile
Gene Regulation
gene transcription
glucocorticoid receptor
histone acetylation
Histones - genetics
Histones - metabolism
Kelch-Like ECH-Associated Protein 1 - genetics
Kelch-Like ECH-Associated Protein 1 - metabolism
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Mice, Knockout
NF-E2-Related Factor 2 - genetics
NF-E2-Related Factor 2 - metabolism
Nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2)
oxidative stress
Oxidative Stress - drug effects
Phosphoproteins - genetics
Phosphoproteins - metabolism
Receptors, Glucocorticoid - genetics
Receptors, Glucocorticoid - metabolism
Signal Transduction - drug effects
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Summary:NRF2 (nuclear factor erythroid 2-related factor 2) is a key transcriptional activator that mediates the inducible expression of antioxidant genes. NRF2 is normally ubiquitinated by KEAP1 (Kelch-like ECH-associated protein 1) and subsequently degraded by proteasomes. Inactivation of KEAP1 by oxidative stress or electrophilic chemicals allows NRF2 to activate transcription through binding to antioxidant response elements (AREs) and recruiting histone acetyltransferase CBP (CREB-binding protein). Whereas KEAP1-dependent regulation is a major determinant of NRF2 activity, NRF2-mediated transcriptional activation varies from context to context, suggesting that other intracellular signaling cascades may impact NRF2 function. To identify a signaling pathway that modifies NRF2 activity, we immunoprecipitated endogenous NRF2 and its interacting proteins from mouse liver and identified glucocorticoid receptor (GR) as a novel NRF2-binding partner. We found that glucocorticoids, dexamethasone and betamethasone, antagonize diethyl maleate-induced activation of NRF2 target genes in a GR-dependent manner. Dexamethasone treatment enhanced GR recruitment to AREs without affecting chromatin binding of NRF2, resulting in the inhibition of CBP recruitment and histone acetylation at AREs. This repressive effect was canceled by the addition of histone deacetylase inhibitors. Thus, GR signaling decreases NRF2 transcriptional activation through reducing the NRF2-dependent histone acetylation. Consistent with these observations, GR signaling blocked NRF2-mediated cytoprotection from oxidative stress. This study suggests that an impaired antioxidant response by NRF2 and a resulting decrease in cellular antioxidant capacity account for the side effects of glucocorticoids, providing a novel viewpoint for the pathogenesis of hypercorticosteroidism.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M116.773960