PI3K mediates tumor necrosis factor induced-necroptosis through initiating RIP1-RIP3-MLKL signaling pathway activation
PI3K mediates tumor necrosis factor induced-necroptosis through initiating RIP1-RIP3-MLKL signaling pathway activation
复制标题
PI3K通过启动RIP1-RIP3-MLKL信号通路激活介导肿瘤坏死因子诱导的坏死性凋亡
DOI：
10.1016/j.cyto.2020.155046
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发表时间：
2020-05-01
期刊：
影响因子：
3.8
通讯作者：
Chen, Guozhu
中科院分区：
文献类型：
--
作者：
Hu, Shiping;Chang, Xixi;Chen, Guozhu
坏死性凋亡是近年来发现的一种程序性细胞死亡，由受体相互作用的丝氨酸/苏氨酸蛋白激酶1（RIP 1）、RIP 3和混合谱系激酶结构域样蛋白（MLKL）启动。已有研究表明，肿瘤坏死因子（TNF）诱导的坏死性凋亡可被磷脂酰肌醇-3-激酶（PI 3 K）抑制剂及其底物蛋白AKT抑制，表明PI 3 K-AKT信号通路参与了TNF诱导的坏死性凋亡，但PI 3 K如何启动坏死性凋亡尚不清楚。在这项研究中，我们发现，TNF诱导的坏死性凋亡抑制化学抑制或基因删除PI 3 K。此外，p110 α，PI 3 K的催化亚基，敲低，显着抑制PI 3 K底物蛋白AKT的磷酸化，TNF诱导的坏死性凋亡被AKT抑制剂阻断。此外，我们发现p110 α敲低也抑制了响应于TNF刺激的RIP 1、RIP 3和MLKL的磷酸化和寡聚化。除了在介导TNF诱导的坏死体形成中的关键作用外，p110 α对RIP 1和RIP 3的自发磷酸化也是必不可少的。最后，我们发现在TNF诱导的坏死性凋亡过程中，p110 α与RIP 3结合形成蛋白复合物，而与RIP 1结合不形成蛋白复合物，并且在RIP 1不存在的情况下介导TNF诱导的坏死性凋亡。我们的研究结果表明，PI 3 K在TNF诱导的坏死性凋亡中是必不可少的，它可能作为RIP 3的伴侣启动RIP 1-RIP 3-MLKL信号通路的激活和随后的坏死性凋亡。
Necroptosis is a recently identified programmed cell death, which is initiated by receptor-interacting serine/threonine-protein kinase 1 (RIP1), RIP3 and mixed-lineage kinase domain-like protein (MLKL). It has been reported that necroptosis induced by tumor necrosis factor (TNF) was inhibited by the inhibitor of phosphatidylinositol-3-kinase (PI3K) and its substrate protein AKT, indicating that PI3K-AKT signaling pathway was involved in mediating TNF-induced necroptosis, whereas it is unclear how PI3K initiates necroptosis. In this study, we found that TNF-induced necroptosis was inhibited by chemical inhibition or genetic deletion of PI3K. Moreover, knockdown of p110 alpha, the catalytic subunit of PI3K, significantly suppressed the phosphorylation of PI3K substrate protein AKT, and TNF-induced necroptosis was blocked by AKT inhibitors. Furthermore, we found that p110 alpha knockdown also suppressed the phosphorylation and oligomerization of RIP1, RIP3 and MLKL in response to TNF stimulation. In addition to the critical role in mediating TNF-induced necrosome formation, p110 alpha was also essential for the spontaneous phosphorylation of RIP1 and RIP3. Finally, we found that p110 alpha bound to RIP3, but not RIP1, to form protein complex in the process of TNF-induced necroptosis, and mediated TNF-induced necroptosis in the absence of RIP1. Our results demonstrate that PI3K is essential for TNF-induced necroptosis, which may act as the partner of RIP3 to initiate the activation of RIP1-RIP3-MLKL signal pathway and the subsequent necroptosis.