棕榈酰转移酶DHHC5调控少突胶质细胞发育的机理研究

髓鞘是维护神经系统信号有效传导的重要结构。蛋白质翻译后修饰在髓鞘发育过程中具有重要意义，但棕榈酰化修饰如何影响髓鞘的发育尚不清楚。在前期工作中，我们发现棕榈酰转移酶Dhhc5基因的缺失抑制小鼠中枢神经系统髓鞘发育，但对外周神经系统无影响。细胞实验显示敲除Dhhc5基因使少突胶质细胞凋亡水平增加。RNA-Seq分析显示，敲除Dhhc5使细胞中JAK-STAT信号通路及细胞凋亡相关基因表达水平发生显著变化。免疫沉淀联合质谱分析显示DHHC5蛋白可与Golga7及STAT3蛋白相结合并棕榈酰化修饰STAT3。Golga7虽不能被DHHC5棕榈酰化修饰，但敲除Golga7可影响DHHC5与STAT3的结合。在后续研究中，我们将结合细胞及动物实验，阐明DHHC5如何与STAT3及Golga7共同作用调节少突胶质细胞凋亡，为阐明少突胶质细胞发育过程的调控机理提供新的思路。

Myelin sheath is an essential structure to maintain the effective signal transduction in the nervous system. Post-translational protein modification plays an important role in myelin development. However, how protein palmitoylation regulates myelination remains unclear. Our preliminary data indicated that the loss of palmitoyl acyltransferase Dhhc5 inhibited myelin formation in the central nervous system, but not in the peripheral nervous system. Knockout of Dhhc5 induced apoptosis in oligodendrocytes. RNA-Seq analysis showed that Dhhc5 knockout altered the JAK-STAT signaling pathway activity and the expression of apoptosis-related genes. Mass-spectrum analysis on the enriched protein immunoprecipitated by DHHC5 revealed that DHHC5 interacted with Golga7 and STAT3, then palmitoylated STAT3. Although Golga7 could not be palmitoylated by DHHC5, knockdown of Golga7 disrupted the interaction between DHHC5 and STAT3. Based on these findings, we will further explore how DHHC5 interacts with Golga7 and STAT3, to regulate the oligodendrocyte development. The proposal aims to reveal a novel mechanism of myelin formation.