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A regulatory module comprising G3BP1-FBXL5-IRP2 axis determines sodium arsenite-induced ferroptosis
Journal of Hazardous Materials ( IF 12.2 ) Pub Date : 2023-12-12 , DOI: 10.1016/j.jhazmat.2023.133038
Qian Liu 1 , Fengli Wang 2 , Yingxian Chen 1 , Hengkang Cui 1 , Hao Wu 1
Journal of Hazardous Materials ( IF 12.2 ) Pub Date : 2023-12-12 , DOI: 10.1016/j.jhazmat.2023.133038
Qian Liu 1 , Fengli Wang 2 , Yingxian Chen 1 , Hengkang Cui 1 , Hao Wu 1
Affiliation
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Arsenic contamination is extremely threatening to the global public health. It was reported that sodium arsenite exposure induces serious kidney injury. However, the underlying mechanism is unclear. Ferroptosis is a newly characterized form of iron-dependent programmed cell death, which is implicated in the pathogenesis of various human diseases, including kidney injury. The lethal accumulation of iron-catalyzed lipid peroxidation is the fundamental biochemical characteristic of ferroptosis. Herein we report that sodium arsenite exposure initiates ferroptosis in mammalian HEK293, MEF and HT1080 cells, and induces ferroptosis-associated acute kidney injury in mice. RNA-binding protein G3BP1, the switch component of stress granules, is indispensable for sodium arsenite-induced ferroptosis in a stress granule-independent manner. Mechanistically, G3BP1 stabilizes IRP2, the master regulator of cellular iron homeostasis, through binding to and suppressing the translation of FBXL5 mRNA, which encodes the E3 ligase component to mediate IRP2 ubiquitination and proteasomal degradation. Sodium arsenite intoxication expedites this G3BP1-FBXL5 -IRP2 axis and elevates cellular labile free iron, which is responsible for sodium arsenite exposure-induced lipid peroxidation and ferroptotic cell death. In summary, this study highlights a regulatory module comprising G3BP1-FBXL5 -IRP2 axis in determining sodium arsenite-induced ferroptosis and ferroptosis-associated acute kidney injury in mice.
中文翻译：
包含 G3BP1-FBXL5-IRP2 轴的调节模块确定亚砷酸钠诱导的铁死亡
砷污染对全球公共卫生构成极大威胁。据报道，亚砷酸钠暴露会导致严重的肾损伤。然而，其潜在机制尚不清楚。铁死亡是一种新特征的铁依赖性程序性细胞死亡形式，它与包括肾损伤在内的各种人类疾病的发病机制有关。铁催化的脂质过氧化的致死性积累是铁死亡的基本生化特征。在此，我们报道亚砷酸钠暴露会启动哺乳动物 HEK293、MEF 和 HT1080 细胞的铁死亡，并诱导小鼠铁死亡相关的急性肾损伤。RNA 结合蛋白 G3BP1 是应激颗粒的开关组分，以不依赖应激颗粒的方式对于亚砷酸钠诱导的铁死亡是必不可少的。从机制上讲，G3BP1 通过结合并抑制 FBXL5 mRNA 的翻译来稳定 IRP2，IRP2 是细胞铁稳态的主要调节因子，FBXL5 mRNA 编码 E3 连接酶组分以介导 IRP2 泛素化和蛋白酶体降解。亚砷酸钠中毒加速了这个 G3BP1-FBXL5-IRP2 轴并升高了细胞不稳定的无铁，这是亚砷酸钠暴露诱导的脂质过氧化和铁死亡细胞的原因。总之，本研究强调了一个包含 G3BP1-FBXL5-IRP2 轴的调节模块，用于确定亚砷酸钠诱导的小鼠铁死亡和铁死亡相关的急性肾损伤。
更新日期：2023-12-12
中文翻译：
包含 G3BP1-FBXL5-IRP2 轴的调节模块确定亚砷酸钠诱导的铁死亡
砷污染对全球公共卫生构成极大威胁。据报道，亚砷酸钠暴露会导致严重的肾损伤。然而，其潜在机制尚不清楚。铁死亡是一种新特征的铁依赖性程序性细胞死亡形式，它与包括肾损伤在内的各种人类疾病的发病机制有关。铁催化的脂质过氧化的致死性积累是铁死亡的基本生化特征。在此，我们报道亚砷酸钠暴露会启动哺乳动物 HEK293、MEF 和 HT1080 细胞的铁死亡，并诱导小鼠铁死亡相关的急性肾损伤。RNA 结合蛋白 G3BP1 是应激颗粒的开关组分，以不依赖应激颗粒的方式对于亚砷酸钠诱导的铁死亡是必不可少的。从机制上讲，G3BP1 通过结合并抑制 FBXL5 mRNA 的翻译来稳定 IRP2，IRP2 是细胞铁稳态的主要调节因子，FBXL5 mRNA 编码 E3 连接酶组分以介导 IRP2 泛素化和蛋白酶体降解。亚砷酸钠中毒加速了这个 G3BP1-FBXL5-IRP2 轴并升高了细胞不稳定的无铁，这是亚砷酸钠暴露诱导的脂质过氧化和铁死亡细胞的原因。总之，本研究强调了一个包含 G3BP1-FBXL5-IRP2 轴的调节模块，用于确定亚砷酸钠诱导的小鼠铁死亡和铁死亡相关的急性肾损伤。
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