RIP3 targets pyruvate dehydrogenase complex to increase aerobic respiration in TNF-induced necroptosis
RIP3 targets pyruvate dehydrogenase complex to increase aerobic respiration in TNF-induced necroptosis
复制标题
RIP3靶向丙酮酸脱氢酶复合物以增加TNF诱导的坏死性凋亡中的有氧呼吸
DOI：
10.1038/s41556-017-0022-y
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发表时间：
2018-02-01
影响因子：
21.3
通讯作者：
Han, Jiahuai
中科院分区：
文献类型：
--
作者：
Yang, Zhentao;Wang, Yan;Han, Jiahuai
受体相互作用蛋白激酶3（RIP 3）调节活性氧（ROS）的产生，对肿瘤坏死因子（TNF）诱导的坏死性凋亡（一种程序性坏死）有正反馈作用。已知谷氨酰胺催化剂有助于RIP 3介导的ROS诱导，但主要贡献者未知。在这里，我们表明，RIP 3激活丙酮酸脱氢酶复合物（PDC，也称为PDH），限速酶连接糖酵解有氧呼吸，直接磷酸化的PDC E3亚基（PDC-E3）T135。在活化后，PDC增强有氧呼吸和随后的线粒体ROS产生。出乎意料的是，混合谱系激酶结构域样（MLKL）也是诱导有氧呼吸所必需的，我们进一步表明RIP 3易位需要它来满足线粒体定位的PDC。我们的数据揭示了PDC活性的调节机制，表明RIP 3激活PDC很可能是TNF激活的主要机制，以增加有氧呼吸及其副产物ROS，并表明RIP 3依赖性诱导有氧呼吸有助于与氧化应激相关的病理学。
Receptor-interacting protein kinase 3 (RIP3)-regulated production of reactive oxygen species (ROS) positively feeds back on tumour necrosis factor (TNF)-induced necroptosis, a type of programmed necrosis. Glutamine catabolism is known to contribute to RIP3-mediated ROS induction, but the major contributor is unknown. Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135. Upon activation, PDC enhances aerobic respiration and subsequent mitochondrial ROS production. Unexpectedly, mixed-lineage kinase domain-like (MLKL) is also required for the induction of aerobic respiration, and we further show that it is required for RIP3 translocation to meet mitochondria-localized PDC. Our data uncover a regulation mechanism of PDC activity, show that PDC activation by RIP3 is most likely the major mechanism activated by TNF to increase aerobic respiration and its by-product ROS, and suggest that RIP3-dependent induction of aerobic respiration contributes to pathologies related to oxidative stress.