PEA15-HKII, Stabilized by U2AF2, Form a Molecular Switch Governing Cellular Fate after Spinal Cord Injury via MAPK Pathway

Spinal cord injury (SCI) is a devastating disease with poor prognosis. In this study, we sought to investigate the effects of proliferation and apoptosis adaptor protein 15 (PEA15) and hexokinase-Ⅱ (HKⅡ) on neuron cells after SCI. Firstly, we established the in vitro SCI model and cultured its neuron cells. Western blot detected the levels of autophagy- and apoptosis-related proteins in SCI neuron cells, and found high levels of LC3-Ⅱ, p62 and CASP12 in SCI neuron cells. Quantitative real time RT-PCR (RT-qPCR) showed the high levels of PEA15 and HKⅡ in SCI neuron cells. Functional experiments verified the positive regulation of PEA15 and HKⅡ on cell apoptosis. Furthermore, PEA15 and HKⅡ promote SCI neuron cell apoptosis by activating mitogen-activated protein kinase (MAPK) pathway. Co-immunoprecipitation (CoIP) and GST pull down assays showed that HKⅡ could interact with phosphorylated PEA15 in SCI neuron cells. Then the interaction of HKⅡ and PEA15-pSer116 was demonstrated to restrain cell apoptosis after SCI. Simultaneously, U2 small nuclear RNA auxiliary factor 2 (U2AF2) could stabilize the mRNA stability of PEA15 and HKⅡ. In summary, PEA15-HKII form a molecular switch to regulate the apoptosis of SCI neuron cells by regulating MAPK pathway, providing a new direction for SCI study.