Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors
Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors
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DOI：
10.1182/blood-2015-06-654194
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发表时间：
2016-01-07
期刊：
影响因子：
20.3
通讯作者：
Greten, Florian R.
中科院分区：
文献类型：
--
作者：
Canli, Oezge;Alankus, Yasemin B.;Greten, Florian R.
维持细胞氧化还原平衡对于细胞存活和组织内稳态是至关重要的，因为活性氧（ROS）的不平衡产生可导致氧化应激和细胞死亡。抗氧化酶谷胱甘肽过氧化物酶4（Gpx4）是氧化应激诱导细胞死亡的关键调节因子。我们发现，在造血细胞中缺失Gpx4的小鼠发生贫血，Gpx4是必不可少的，以防止受体相互作用蛋白3（RIP3）依赖性坏死性凋亡的红系前体细胞。Gpx4的缺失导致谷胱甘肽化导致半胱天冬酶8功能失活，导致坏死性凋亡，其独立于肿瘤坏死因子a活化而发生。虽然Rip3基因的去除使网织红细胞成熟正常化并防止贫血，但Gpx4缺陷细胞中的ROS积累和脂质过氧化仍然很高。我们的研究结果表明，活性氧和脂质过氧化氢的功能尚未认识到的RIP3依赖性坏死性凋亡的非常规上游信号激活剂。
Maintaining cellular redox balance is vital for cell survival and tissue homoeostasis because imbalanced production of reactive oxygen species (ROS) may lead to oxidative stress and cell death. The antioxidant enzyme glutathione peroxidase 4 (Gpx4) is a key regulator of oxidative stress-induced cell death. We show that mice with deletion of Gpx4 in hematopoietic cells develop anemia and that Gpx4 is essential for preventing receptor-interacting protein 3 (RIP3)-dependent necroptosis in erythroid precursor cells. Absence of Gpx4 leads to functional inactivation of caspase 8 by glutathionylation, resulting in necroptosis, which occurs independently of tumor necrosis factor a activation. Although genetic ablation of Rip3 normalizes reticulocyte maturation and prevents anemia, ROS accumulation and lipid peroxidation in Gpx4-deficient cells remain high. Our results demonstrate that ROS and lipid hydroperoxides function as not-yet-recognized unconventional upstream signaling activators of RIP3-dependent necroptosis.