論文 - 詳細
| RRC ID | 74791 |
|---|---|
| 著者 | Van Hall-Beauvais A, Poganik JR, Huang KT, Parvez S, Zhao Y, Lin HY, Liu X, Long MJC, Aye Y. |
| タイトル | Z-REX uncovers a bifurcation in function of Keap1 paralogs. |
| ジャーナル | Elife |
| Abstract |
Studying electrophile signaling is marred by difficulties in parsing changes in pathway flux attributable to on-target, vis-à-vis off-target, modifications. By combining bolus dosing, knockdown, and Z-REX-a tool investigating on-target/on-pathway electrophile signaling, we document that electrophile labeling of one zebrafish-Keap1-paralog (zKeap1b) stimulates Nrf2- driven antioxidant response (AR) signaling (like the human-ortholog). Conversely, zKeap1a is a dominant-negative regulator of electrophile-promoted Nrf2-signaling, and itself is nonpermissive for electrophile-induced Nrf2-upregulation. This behavior is recapitulated in human cells: (1) zKeap1b-expressing cells are permissive for augmented AR-signaling through reduced zKeap1b-Nrf2 binding following whole-cell electrophile treatment; (2) zKeap1a-expressing cells are non-permissive for AR-upregulation, as zKeap1a-Nrf2 binding capacity remains unaltered upon whole-cell electrophile exposure; (3) 1:1 ZKeap1a:zKeap1b-co-expressing cells show no Nrf2-release from the Keap1-complex following whole-cell electrophile administration, rendering these cells unable to upregulate AR. We identified a zKeap1a-specific point-mutation (C273I) responsible for zKeap1a's behavior during electrophilic stress. Human-Keap1(C273I), of known diminished Nrf2-regulatory capacity, dominantly muted electrophile-induced Nrf2-signaling. These studies highlight divergent and interdependent electrophile signaling behaviors, despite conserved electrophile sensing. |
| 巻・号 | 11 |
| 公開日 | 2022-10-27 |
| DOI | 10.7554/eLife.83373 |
| PII | 83373 |
| PMID | 36300632 |
| PMC | PMC9754640 |
| MeSH | Animals Antioxidants / metabolism Humans Kelch-Like ECH-Associated Protein 1 / genetics Kelch-Like ECH-Associated Protein 1 / metabolism NF-E2-Related Factor 2* / genetics NF-E2-Related Factor 2* / metabolism Signal Transduction Zebrafish* / metabolism |
| IF | 7.08 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 7 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ゼブラフィッシュ | Tg(-3.5gstp1:GFP)it416b |