Accumulation of RIPK1 into mitochondria is requisite for oxidative stress-mediated necroptosis and proliferation in Rat Schwann cells.
Accumulation of RIPK1 into mitochondria is requisite for oxidative stress-mediated necroptosis and proliferation in Rat Schwann cells.
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DOI：
10.7150/ijms.69992
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发表时间：
2022
影响因子：
3.6
通讯作者：
Chen M
中科院分区：
文献类型：
--
作者：
Wang B;Fu J;Chai Y;Liu Y;Chen Y;Yin J;Pu Y;Chen C;Wang F;Liu Z;Zheng L;Chen M
雪旺细胞损伤是周围神经病变的重要病理特征。然而，明确的分子机制和阻断方法仍有待探索。在这项研究中，我们确定了坏死坏死的关键执行子ripk1，在大鼠雪旺细胞氧化应激诱导的损伤中发挥了独特的功能。我们发现H2O2模拟氧化应激后，RIPK1的激活不依赖于基因上调，而是通过翻译后修饰，包括其蛋白水平、丝氨酸166和丝氨酸321位点磷酸化以及泛素化水平。在共聚焦显微镜下，我们发现RIPK1明显积聚在线粒体中。免疫沉淀显示，线粒体RIPK1的磷酸化、泛素化水平也升高。通过给药n - acetyl - l-半胱氨酸（NAC），一种ROS抑制剂，我们发现RIPK1的磷酸化、泛素化和线粒体定位被显著抑制。而施用Necrostatin-1 （Nec-1）未能影响ROS水平和线粒体膜电位，表明RIPK1是ROS的下游调节因子。最后，通过Annexin V/PI评估、CCK-8检测、TEM扫描和EdU染色显示，Nec-1对RIPK1的药理抑制降低了坏死坏死的水平，增加了增殖。我们的研究结果表明，在雪旺细胞中，RIPK1在氧化应激反应中存在先前未被识别的翻译后变化。
The injury of Schwann cells is an important pathological feature of peripheral neuropathy. However, the explicit molecular mechanism and blocking method remains to be explored. In this study, we identified an pivotal executor of necroptosis—RIPK1, performed an unique function in response to oxidative stress-induced injury in Rat Schwann cells. We found that after oxidative stress-simulation by H2O2, RIPK1 was activated independent of genetic up-regulation, but through the post-translational modification, including its protein levels, phosphorylation of Serine 166 and Serine 321 sites and its general ubiquitination levels. Under a confocal microscopy, we found that RIPK1 was significantly accumulated into the mitochondria. And the phosphorylation, ubiquitination levels were also elevated in mitochondrial RIPK1, as indicated by immunoprecipitation. Through the administration of N-Acetyl-L-cysteine (NAC), a ROS inhibitor, we found that the phosphorylation, ubiquitination and mitochondrial location of RIPK1 was significantly suppressed. While administration of Necrostatin-1 (Nec-1) failed to influence the levels of ROS and mitochondrial membrane potential, revealing that RIPK1 served as the down-stream regulators of ROS. Lastly, pharmacological inhibition of RIPK1 by Nec-1 attenuated the levels of necroptosis, increased proliferation, as indicated by Annexin V/PI evaluation, CCK-8 detection, TEM scanning and EdU staining. Our results indicate a previous un-recognized post-translational change of RIPK1 in response to oxidative stress in Schwann cells.
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影响因子：
25
作者：
Dombrowski Y;O'Hagan T;Dittmer M;Penalva R;Mayoral SR;Bankhead P;Fleville S;Eleftheriadis G;Zhao C;Naughton M;Hassan R;Moffat J;Falconer J;Boyd A;Hamilton P;Allen IV;Kissenpfennig A;Moynagh PN;Evergren E;Perbal B;Williams AC;Ingram RJ;Chan JR;Franklin RJM;Fitzgerald DC
通讯作者：
Fitzgerald DC
DOI：
10.1073/pnas.1605195113
发表时间：
2016-10-25
影响因子：
11.1
作者：
Dong, Yun;Fischer, Roman;Eisel, Ulrich L. M.
通讯作者：
Eisel, Ulrich L. M.
影响因子：
3
作者：
Kernisant, Melanie;Gear, Robert W.;Ohara, Peter T.
通讯作者：
Ohara, Peter T.
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影响因子：
21.3
作者：
Lafont E;Draber P;Rieser E;Reichert M;Kupka S;de Miguel D;Draberova H;von Mässenhausen A;Bhamra A;Henderson S;Wojdyla K;Chalk A;Surinova S;Linkermann A;Walczak H
通讯作者：
Walczak H
影响因子：
7.4
作者：
Finnerup, Nanna Brix;Sindrup, Soren Hein;Jensen, Troels Staehelin
通讯作者：
Jensen, Troels Staehelin