Cyclin-dependent kinase 5-mediated phosphorylation of chloride intracellular channel 4 promotes oxidative stress-induced neuronal death.
Cyclin-dependent kinase 5-mediated phosphorylation of chloride intracellular channel 4 promotes oxidative stress-induced neuronal death.
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细胞周期蛋白依赖性激酶 5 介导的氯离子通道 4 磷酸化促进氧化应激诱导的神经元死亡
DOI：
10.1038/s41419-018-0983-1
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发表时间：
2018-09-20
影响因子：
9
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Guo D;Xie W;Xiong P;Li H;Wang S;Chen G;Gao Y;Zhou J;Zhang Y;Bu G;Xue M;Zhang J
氧化应激可引起神经元细胞凋亡，并可能导致神经退行性疾病。然而，导致氧化应激诱导的神经元凋亡的信号机制尚不完全清楚。氧化应激刺激细胞周期蛋白依赖性激酶5 （CDK5）的异常激活，被认为通过磷酸化许多细胞死亡相关底物来促进神经元凋亡。在这里，通过蛋白下拉法、免疫荧光实验和体外激酶测定，我们确定了氯离子胞内通道4 （CLIC4）作为CDK5底物，其表达在神经元凋亡过程中增加。我们发现活化的CDK5磷酸化了CLIC4中的丝氨酸108，增加了CLIC4蛋白的稳定性和积累。药物抑制或shrna介导的CDK5沉默可降低神经元中CLIC4的水平。此外，CLIC4过表达导致神经元凋亡，而敲低或药物抑制CLIC4可减轻h2o2诱导的神经元凋亡。这些结果表明，CLIC4作为CDK5的底物，介导了CDK5异常活化诱导的神经元凋亡。因此，在神经元中靶向CLIC4可能为治疗由神经元凋亡引起的进行性神经退行性疾病提供一种治疗方法。
Oxidative stress can cause apoptosis in neurons and may result in neurodegenerative diseases. However, the signaling mechanisms leading to oxidative stress–induced neuronal apoptosis are not fully understood. Oxidative stress stimulates aberrant activation of cyclin-dependent kinase 5 (CDK5), thought to promote neuronal apoptosis by phosphorylating many cell death-related substrates. Here, using protein pulldown methods, immunofluorescence experiments and in vitro kinase assays, we identified chloride intracellular channel 4 (CLIC4), the expression of which increases during neuronal apoptosis, as a CDK5 substrate. We found that activated CDK5 phosphorylated serine 108 in CLIC4, increasing CLIC4 protein stability, and accumulation. Pharmacological inhibition or shRNA-mediated silencing of CDK5 decreased CLIC4 levels in neurons. Moreover, CLIC4 overexpression led to neuronal apoptosis, whereas knockdown or pharmacological inhibition of CLIC4 attenuated H2O2-induced neuronal apoptosis. These results implied that CLIC4, by acting as a substrate of CDK5, mediated neuronal apoptosis induced by aberrant CDK5 activation. Targeting CLIC4 in neurons may therefore provide a therapeutic approach for managing progressive neurodegenerative diseases that arise from neuronal apoptosis.
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影响因子：
4.2
作者：
Brooks, PJ
通讯作者：
Brooks, PJ
影响因子：
4.8
作者：
Aon, Miguel A.;Cortassa, Sonia;O'Rourke, Brian
通讯作者：
O'Rourke, Brian
Clic4，一种新型蛋白质，可将β细胞敏感到细胞凋亡。
影响因子：
8.1
作者：
Patel D;Ythier D;Brozzi F;Eizirik DL;Thorens B
通讯作者：
Thorens B
影响因子：
5.4
作者：
He, Guoan;Ma, Yao;Chou, Szu-Yi;Li, Huihong;Yang, Chingwen;Chuang, Jen-Zen;Sung, Ching-Hwa;Ding, Aihao
通讯作者：
Ding, Aihao
影响因子：
20.1
作者：
Spiekerkoetter E;Guignabert C;de Jesus Perez V;Alastalo TP;Powers JM;Wang L;Lawrie A;Ambartsumian N;Schmidt AM;Berryman M;Ashley RH;Rabinovitch M
通讯作者：
Rabinovitch M