RIP3, an Energy Metabolism Regulator That Switches TNF-Induced Cell Death from Apoptosis to Necrosis
RIP3, an Energy Metabolism Regulator That Switches TNF-Induced Cell Death from Apoptosis to Necrosis
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DOI：
10.1126/science.1172308
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发表时间：
2009-07-17
期刊：
影响因子：
56.9
通讯作者：
Han, Jiahuai
中科院分区：
文献类型：
--
作者：
Zhang, Duan-Wu;Shao, Jing;Han, Jiahuai
用肿瘤坏死因子或其他激动剂刺激死亡受体可诱导坏死，但其区别于细胞凋亡的潜在机制尚不清楚。我们鉴定了蛋白激酶受体相互作用蛋白3(RIP3)是肿瘤坏死因子诱导NIH3T3细胞凋亡和坏死之间的分子开关，并发现其他细胞的坏死也需要RIP3。RIP3不影响RIP1介导的细胞凋亡，但对于RIP1介导的坏死和caspase抑制剂zVAD增强坏死是必需的。通过激活代谢途径的关键酶，RIP3调节肿瘤坏死因子诱导的活性氧的产生，这部分解释了RIP3的S促进坏死的能力。我们的数据表明，对死亡刺激的能量代谢的调节在细胞凋亡和坏死之间的选择中起着重要的作用。
Necrosis can be induced by stimulating death receptors with tumor necrosis factor (TNF) or other agonists; however, the underlying mechanism differentiating necrosis from apoptosis is largely unknown. We identified the protein kinase receptor-interacting protein 3 (RIP3) as a molecular switch between TNF-induced apoptosis and necrosis in NIH 3T3 cells and found that RIP3 was required for necrosis in other cells. RIP3 did not affect RIP1-mediated apoptosis but was required for RIP1-mediated necrosis and the enhancement of necrosis by the caspase inhibitor zVAD. By activating key enzymes of metabolic pathways, RIP3 regulates TNF-induced reactive oxygen species production, which partially accounts for RIP3's ability to promote necrosis. Our data suggest that modulation of energy metabolism in response to death stimuli has an important role in the choice between apoptosis and necrosis.