由代谢物衍生的蛋白质修饰将糖解与KEAP1-NRF2信号结合起来
Michael J Bollong1, Gihoon Lee2,3, John S Coukos2,3
1Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Nature
|October 17, 2018
概括
抑制糖解酶PGK1会增加反应性甲基,从而改变KEAP1. 这激活了NRF2抗氧化反应,将糖解与细胞应激防御联系起来.
科学领域:
- 生物化学
- 分子生物学
- 细胞代谢
背景情况:
- 细胞平衡依赖于将新陈代谢状态与调节途径相结合.
- 反应性代谢物可以共价地改变蛋白质,影响代谢和转录等细胞功能.
- KEAP1作为反应性物种的传感器,调节NRF2介导的抗氧化反应.
研究的目的:
- 确定糖解与NRF2信号通路之间的联系.
- 研究糖解抑制对细胞应激反应的影响机制.
- 探索针对KEAP1-NRF2轴的潜在治疗策略.
主要方法:
- 抑制糖解酶糖酸激酶1 (PGK1) 的作用.
- 对反应性代谢物积累的分析,特别是甲基.
- 描述KEAP1的共价变异及其对NRF2水平和活性的影响.
- 评估NRF2介导的转录激活.
主要成果:
- 抑制PGK1导致甲基素的积累.
- 在氨酸和氨酸残留物之间形成甲基利米达交叉连接 (MICA).
- KEAP1的修改导致其二元化,NRF2的积累和NRF2转录程序的激活.
- 葡萄糖分解与KEAP1-NRF2途径之间有直接的沟通.
结论:
- 糖解直接影响KEAP1-NRF2转录轴.
- 在细胞应激反应中,基甲基素介导的KEAP1修饰是关键的调节机制.
- 这一途径代表了涉及抗氧化反应的疾病的潜在治疗点.
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