Department of Neurobiology, School of life Sciences, China Medical University, Shenyang, China.
Key Laboratory of Neuro-Oncology in Liaoning Province, Shenyang, China.
J Cereb Blood Flow Metab. 2024 Sep;44(9):1655-1673. doi: 10.1177/0271678X241240590. Epub 2024 Mar 21.
Chronic cerebral ischemia (CCI) is a clinical syndrome characterised by brain dysfunction due to decreased chronic cerebral perfusion. CCI initiates several inflammatory pathways, including pyroptosis. RNA-binding proteins (RBPs) play important roles in CCI. This study aimed to explore whether the interaction between RBP-Cpeb4 and Dclk2 affected Ehf phosphorylation to regulate neuronal pyroptosis. HT22 cells and mice were used to construct oxygen glucose deprivation (OGD)/CCI models. We found that Cpeb4 and Dclk2 were upregulated in OGD-treated HT22 cells and CCI-induced hippocampal CA1 tissues. Cpeb4 upregulated Dclk2 expression by increasing Dclk2 mRNA stability. Knockdown of Cpeb4 or Dclk2 inhibited neuronal pyroptosis in OGD-treated HT22 cells and CCI-induced hippocampal CA1 tissues. By binding to the promoter regions of Caspase1 and Caspase3, the transcription factor Ehf reduced their promoter activities and inhibited the transcription. Dclk2 phosphorylated Ehf and changed its nucleoplasmic distribution, resulting in the exit of p-Ehf from the nucleus and decreased Ehf levels. It promoted the expression of Caspase1 and Caspase3 and stimulated neuronal pyroptosis of HT22 cells induced by OGD. Cpeb4/Dclk2/Ehf pathway plays an important role in the regulation of cerebral ischemia-induced neuronal pyroptosis.
慢性脑缺血（CCI）是一种由于慢性脑灌注减少导致脑功能障碍的临床综合征。CCI 引发了几种炎症途径，包括细胞焦亡。RNA 结合蛋白（RBPs）在 CCI 中发挥重要作用。本研究旨在探讨 RBP-Cpeb4 和 Dclk2 之间的相互作用是否通过影响 Ehf 磷酸化来调节神经元细胞焦亡。使用 HT22 细胞和小鼠构建氧葡萄糖剥夺（OGD）/CCI 模型。我们发现，Cpeb4 和 Dclk2 在 OGD 处理的 HT22 细胞和 CCI 诱导的海马 CA1 组织中上调。Cpeb4 通过增加 Dclk2 mRNA 的稳定性来上调 Dclk2 的表达。敲低 Cpeb4 或 Dclk2 抑制了 OGD 处理的 HT22 细胞和 CCI 诱导的海马 CA1 组织中的神经元细胞焦亡。转录因子 Ehf 通过结合 Caspase1 和 Caspase3 的启动子区域，降低其启动子活性并抑制转录。Dclk2 磷酸化 Ehf 并改变其核质分布，导致 p-Ehf 从核内逸出并降低 Ehf 水平。它促进了 Caspase1 和 Caspase3 的表达，刺激了 OGD 诱导的 HT22 细胞的神经元细胞焦亡。Cpeb4/Dclk2/Ehf 通路在调节脑缺血诱导的神经元细胞焦亡中起重要作用。
