通过调节GPX4和铁信号传递,MMP9驱动铁亡
Flobater I Gawargi1, Paras K Mishra1
1Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA.
iScience
|September 10, 2024
概括
矩阵金属蛋白酶-9 (MMP9) 关键调节铁,一种由铁过载和谷氨过氧化酶-4 (GPX4) 抑制驱动的细胞死亡形式. MMP9影响GPX4水平,铁平衡和细胞氧化还原状态,提供了一个潜在的治疗点.
科学领域:
- 细胞生物学 细胞生物学
- 生物化学 生物化学
- 分子医学是分子医学.
背景情况:
- 铁亡是一种受调节的细胞死亡途径,其特点是抑制谷氨过氧化酶-4 (GPX4) 和铁的积累.
- 了解控制铁亡的分子机制对于开发向疗法至关重要.
研究的目的:
- 研究矩阵金属蛋白酶-9 (MMP9) 在调节铁亡中的作用.
- 阐明MMP9影响铁亡的分子相互作用和途径.
主要方法:
- 使用了一种创新的MMP9构造,缺乏原酶活性.
- 使用液体染色学-质谱学/质谱学 (LC-MS/MS) 来识别蛋白质相互作用体.
- 进行综合通路分析 (IPA) 来分析受影响的细胞通路.
主要成果:
- 活跃的MMP9直接与GPX4和谷氨还原酶相互作用,降低GPX4的表达和活性.
- MMP9抑制了关键的转录因子 (SP1,CREB1,NRF2,FOXO3,ATF4),GPX1和铁灭抑制蛋白-1 (FSP1),破坏了细胞的氧化还原平衡.
- MMP9调节铁代谢,并与参与铁灭调节的83种亚细胞蛋白相互作用.
结论:
- MMP9是铁灭的重要调节者,影响GPX4,铁稳定和细胞氧化还原平衡.
- MMP9对铁亡途径的广泛影响表明,它有可能成为涉及氧化还原和铁失调的疾病的治疗标.
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