RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome.
RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome.
复制标题
RIP1 自磷酸化由线粒体 ROS 促进，对于 RIP3 募集到坏死体至关重要
DOI：
10.1038/ncomms14329
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发表时间：
2017-02-08
影响因子：
16.6
通讯作者：
Han J
中科院分区：
文献类型：
--
作者：
Zhang Y;Su SS;Zhao S;Yang Z;Zhong CQ;Chen X;Cai Q;Yang ZH;Huang D;Wu R;Han J
坏死性凋亡是一种程序性细胞死亡，在许多病理过程中具有重要意义。肿瘤坏死因子-α（TNF）是一种促炎细胞因子，是坏死性凋亡的原型触发因子。已知线粒体活性氧（ROS）促进坏死性凋亡，并且TNF诱导的坏死性凋亡需要受体相互作用蛋白1（RIP 1）的激酶活性。然而，ROS如何发挥作用以及RIP 1磷酸化促进坏死性凋亡在很大程度上是未知的。在这里，我们表明，RIP 1中的三个关键的半胱氨酸是传感ROS所必需的，ROS随后激活RIP 1丝氨酸残基161（S161）上的自磷酸化。RIP 1激酶活性在TNF诱导的坏死性凋亡中的主要功能是使S161自磷酸化。这种特异性磷酸化使RIP 1能够募集RIP 3并形成功能性坏死体，这是坏死性凋亡的中央控制器。由于已知ROS诱导需要坏死体RIP 3，因此ROS在确保有效诱导坏死性凋亡的正反馈回路中起作用。线粒体活性氧（ROS）促进坏死性凋亡，受体相互作用蛋白1（RIP 1）是这种形式的细胞死亡的关键参与者。在这里，作者表明RIP 1中的半胱氨酸残基感知ROS，半胱氨酸的氧化触发RIP 1自磷酸化，这促进了功能性坏死体的形成。
Necroptosis is a type of programmed cell death with great significance in many pathological processes. Tumour necrosis factor-α(TNF), a proinflammatory cytokine, is a prototypic trigger of necroptosis. It is known that mitochondrial reactive oxygen species (ROS) promote necroptosis, and that kinase activity of receptor interacting protein 1 (RIP1) is required for TNF-induced necroptosis. However, how ROS function and what RIP1 phosphorylates to promote necroptosis are largely unknown. Here we show that three crucial cysteines in RIP1 are required for sensing ROS, and ROS subsequently activates RIP1 autophosphorylation on serine residue 161 (S161). The major function of RIP1 kinase activity in TNF-induced necroptosis is to autophosphorylate S161. This specific phosphorylation then enables RIP1 to recruit RIP3 and form a functional necrosome, a central controller of necroptosis. Since ROS induction is known to require necrosomal RIP3, ROS therefore function in a positive feedback circuit that ensures effective induction of necroptosis. Mitochondrial reactive oxygen species (ROS) promote necroptosis and the receptor interacting protein 1 (RIP1) is a key player in this form of cell death. Here, the authors show that cysteine residues in RIP1 sense ROS and oxidation of the cysteines triggers RIP1 autophosphorylation, which promotes functional necrosome formation.