Akt and mTOR mediate programmed necrosis in neurons.
Akt and mTOR mediate programmed necrosis in neurons.
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Akt 和 mTOR 介导神经元程序性坏死
DOI：
10.1038/cddis.2014.69
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发表时间：
2014-02-27
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
坏死性下垂是一种新描述的调节性坏死形式，在中风和脑创伤的实验模型中导致神经元死亡。虽然已经做了许多工作来阐明启动机制，但控制坏死性下垂的信号事件在很大程度上仍未被探索。已知AKT能抑制神经细胞的凋亡。雷帕霉素的机制靶点(MTOR)是Akt的下游效应因子，控制蛋白质的合成。我们之前曾报道，双重抑制Akt和mTOR可以减少急性细胞死亡，并改善受控皮质撞击后小鼠的长期认知障碍。这些发现增加了Akt/mTOR可能调节坏死性下垂的可能性。为了验证这一假设，我们使用肿瘤坏死因子和泛半胱氨酸蛋白酶抑制剂N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone.联合治疗，诱导了海马神经元系hT22细胞的坏死性下垂。肿瘤坏死因子α/zVAD诱导细胞在4h内死亡，在细胞死亡之前，RIPK1-RIPK3-PAKT组装、Thr-308和Thr473、β及其直接底物糖原合成酶-3β以及mTOR及其直接底物S6核糖体蛋白(S6)被磷酸化，提示AKT/mTOR通路被激活。在不影响RIPK1-RIPK3复合体组装的情况下，Akt抑制剂VIII和雷帕霉素可抑制Akt和S6的磷酸化事件、线粒体活性氧的产生和坏死性下垂超过50%。这些数据通过小分子抑制性核糖核酸介导的AKT1/2和mTOR基因敲除得到证实。所有上述生化事件均被Necrostatin-1抑制，包括Akt和mTor的磷酸化、氧化应激的产生和RIPK1-RIPK3-PACKT复合体的组装。这些数据表明，到目前为止，Akt和mTOR在RIPK1激活下游在神经细胞死亡中发挥了一个新的、迄今为止意想不到的作用。
Necroptosis is a newly described form of regulated necrosis that contributes to neuronal death in experimental models of stroke and brain trauma. Although much work has been done elucidating initiating mechanisms, signaling events governing necroptosis remain largely unexplored. Akt is known to inhibit apoptotic neuronal cell death. Mechanistic target of rapamycin (mTOR) is a downstream effector of Akt that controls protein synthesis. We previously reported that dual inhibition of Akt and mTOR reduced acute cell death and improved long term cognitive deficits after controlled-cortical impact in mice. These findings raised the possibility that Akt/mTOR might regulate necroptosis. To test this hypothesis, we induced necroptosis in the hippocampal neuronal cell line HT22 using concomitant treatment with tumor necrosis factor α (TNFα) and the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. TNFα/zVAD treatment induced cell death within 4 h. Cell death was preceded by RIPK1–RIPK3–pAkt assembly, and phosphorylation of Thr-308 and Thr473 of AKT and its direct substrate glycogen synthase kinase-3β, as well as mTOR and its direct substrate S6 ribosomal protein (S6), suggesting activation of Akt/mTOR pathways. Pretreatment with Akt inhibitor viii and rapamycin inhibited Akt and S6 phosphorylation events, mitochondrial reactive oxygen species production, and necroptosis by over 50% without affecting RIPK1–RIPK3 complex assembly. These data were confirmed using small inhibitory ribonucleic acid-mediated knockdown of AKT1/2 and mTOR. All of the aforementioned biochemical events were inhibited by necrostatin-1, including Akt and mTOR phosphorylation, generation of oxidative stress, and RIPK1–RIPK3–pAkt complex assembly. The data suggest a novel, heretofore unexpected role for Akt and mTOR downstream of RIPK1 activation in neuronal cell death.
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影响因子：
3.7
作者：
McNamara CR;Ahuja R;Osafo-Addo AD;Barrows D;Kettenbach A;Skidan I;Teng X;Cuny GD;Gerber S;Degterev A
通讯作者：
Degterev A
RIP1激酶在介导TNFα产生中的新作用。
影响因子：
9
作者：
通讯作者：
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影响因子：
16
作者：
Kim, You-Sun;Morgan, Michael J.;Liu, Zheng-Gang
通讯作者：
Liu, Zheng-Gang
影响因子：
4.8
作者：
Kilic, E;Kilic, Ü;Hermann, DM
通讯作者：
Hermann, DM
影响因子：
6.1
作者：
Friguls, B;Petegnief, V;Planas, AM
通讯作者：
Planas, AM