Cpeb4-mediated Dclk2 promotes neuronal pyroptosis induced by chronic cerebral ischemia through phosphorylation of Ehf

Author:

Sun Miao12ORCID,Huang Xin3,Ruan Xuelei12,Shang Xiuli4,Zhang Mengyang12,Liu Libo12,Wang Ping12,An Ping12,Lin Yang12,Yang Jin25,Xue Yixue12

Affiliation:

1. Department of Neurobiology, School of life Sciences, China Medical University, Shenyang, China

2. Key Laboratory of Neuro-Oncology in Liaoning Province, Shenyang, China

3. Department of Radiology, The First Affiliated Hospital of China Medical University, Shenyang, China

4. Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, China

5. Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China

Abstract

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.

Publisher

SAGE Publications

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