乳化修改HIF-1α通过阻止VHL识别来提高其稳定性
Chengyu Li1, Chen Fu1, Wenhan Zhou1
1College of Animal Science and Technology, Nanjing Agricultural University, Weigang 1, Nanjing, 210095, China.
Cell communication and signaling : CCS
|August 5, 2025
概括
乳酸盐通过lysine乳酸化修改缺氧诱导因子1α (HIF-1α),通过阻止其降解来稳定蛋白质. 这种代谢调节增强了HIF-1α.
科学领域:
- 细胞生物学 细胞生物学
- 代谢过程中的代谢.
- 分子生物学分子生物学
背景情况:
- 低氧诱导因子1α (HIF-1α) 调节细胞适应低氧条件.
- HIF-1α的稳定性主要通过基化和随后通过·希佩尔-林道 (VHL) 泛化复合体降解来控制.
- 乳酸对HIF-1α稳定通过翻译后修改的影响尚未完全理解.
研究的目的:
- 研究乳酸诱导后翻译修饰在HIF-1α稳定中的作用.
- 确定乳酸介导的HIF-1α调节的特定部位和机制.
- 探索乳酸化对HIF-1α活性的功能后果.
主要方法:
- 质谱测量以确定HIF-1α上的乳化部位.
- 位点定向突变发生,以评估乳糖化对功能影响.
- VHL结合测定和无处不在研究.
- 记者测定和基因表达分析以评估HIF-1α转录活性.
- 跨物种的比较分析.
主要成果:
- 乳酸盐诱导了HIF-1α在保存 (人类/猪中的K12) 和分离 (小鼠中的K644) 残留物中的lysine乳酸化.
- 乳化损害了VHL识别,并减少了K48相关的泛化和蛋白质体降解,即使是基化.
- 乳酸化HIF-1α显示出增加的转录活性,上调低氧反应基因,如Vegfa和Glut1.1.
- 结构建模证实乳糖化在无影响氧化的情况下,在硬质上阻碍了VHL结合.
结论:
- 乳化是一种新的,进化保守的稳定HIF-1α的机制.
- 这种修改取代了常规的氧化依赖的降解途径.
- 代谢状态,通过乳酸,通过HIF-1α乳化直接影响低氧信号.
- 研究结果揭示了对细胞对低氧反应的新一层代谢控制.
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