Sp1 is a substrate of Keap1 and regulates the activity of CRL4AWDR23 ubiquitin ligase toward Nrf2
| العنوان: | Sp1 is a substrate of Keap1 and regulates the activity of CRL4AWDR23 ubiquitin ligase toward Nrf2 |
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| المؤلفون: | Ferbian Milas Siswanto, Ami Oguro, Susumu Imaoka |
| المصدر: | The Journal of Biological Chemistry |
| بيانات النشر: | American Society for Biochemistry and Molecular Biology, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, DNA damage-binding protein 1, CUL4A, Cullin 4A, Cullin4A, RBX1, Ring-box 1, Biochemistry, Nrf2, nuclear factor erythroid 2-related factor 2, nuclear factor 2 (erythroid-derived 2-like factor), Ubiquitin, oxidative stress, Post-translational regulation, HO-1, heme oxygenase-1, biology, Chemistry, DDB1, DNA damage-binding protein 1, Sp1, specificity protein 1, Ubiquitin ligase, Cell biology, Keap1, Kelch-like ECH-associated protein 1, Kelch-Like ECH-Associated Protein 1, Ubiquitin ligase complex, shRNA, short hairpin RNA, Cullin, Research Article, NF-E2-Related Factor 2, Sp1 Transcription Factor, Ubiquitin-Protein Ligases, posttranslational regulation, ARE, antioxidant response elements, Kelch-like ECH-associated protein 1, CRL4, Cullin 4-RING ligase, 03 medical and health sciences, DDB1, WD40 repeat protein 23, Cell Line, Tumor, Cullin 4A-RING ligase, Humans, specificity protein 1, Molecular Biology, KD, knockdown, 030102 biochemistry & molecular biology, Cell Biology, Ring-box 1, Kinetics, 030104 developmental biology, Gene Expression Regulation, biology.protein, CUL4A, gene regulation, NQO1, NAD(P)H quinone dehydrogenase 1, WDR23, WD40 repeat protein 23 |
| الوصف: | Nuclear factor erythroid 2–related factor 2 (Nrf2) is a critical transcription factor that orchestrates cellular responses to oxidative stress. Because the dysregulation of Nrf2 has been implicated in many diseases, precise regulation of its protein level is crucial for maintaining homeostasis. Kelch-like-ECH-associated protein 1 (Keap1) and WD40 repeat protein 23 (WDR23) directly regulate Nrf2 levels via similar but distinct proteasome-dependent pathways. WDR23 forms a part of the WDR23-Cullin 4A-RING ubiquitin ligase complex (CRL4AWDR23), whereas Keap1 serves as a substrate adaptor for the Cullin 3–containing ubiquitin ligase complex. However, the mechanisms underlying crosstalk between these Keap1 and WDR23 pathways for the regulation of Nrf2 levels have not been investigated. Here, we showed that knockdown (KD) of Keap1 upregulated the expression of Cullin4A (CUL4A) in a specificity protein 1 (Sp1)–dependent manner. We also revealed that Sp1 interacted with Keap1, leading to ubiquitination of Sp1. Increases in Sp1 by Keap1 KD triggered Sp1 binding to the fourth Sp1 binding site (Sp1_M4) within the −230/+50 region of the CUL4A gene. We also demonstrated that the overexpression and KD of Sp1 reduced and increased Nrf2 protein levels, respectively. These effects were abrogated by the WDR23 KD, suggesting that Sp1 also regulates Nrf2 levels via the ubiquitin ligase complex CRL4AWDR23. In conclusion, we discovered Sp1 as a novel substrate of Keap1 and provided evidence that Sp1 regulates the expression of CUL4A. We revealed a novel role for Sp1 in mediating crosstalk between two independent regulators of Nrf2 protein levels. |
| اللغة: | English |
| تدمد: | 1083-351X 0021-9258 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::707cf01346d6f8bd9189f7ef3b137d58 http://europepmc.org/articles/PMC8141886 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....707cf01346d6f8bd9189f7ef3b137d58 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1083351X 00219258 |
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