Department of Biochemistry and Molecular Biology, Nanjing Medical University, Jiangsu, China.
FEBS Lett. 2012 May 7;586(9):1259-64. doi: 10.1016/j.febslet.2012.03.048. Epub 2012 Mar 31.
Protein SUMOylation has been implicated in the pathogenesis of ischemic stroke. However, the underlying mechanisms remain unclear. Here, we found that global brain ischemia evokes a sustained elevation of GluK2 SUMOylation in the rat hippocampal CA1 region. Over-expression of wild-type GluK2, but not SUMOylation-deficient mutant, significantly increased the activity of MLK3 and JNK3 after kainate stimulation. SUMOylation deficiency attenuated the kainate-stimulated interaction between MLK3 and GluK2. In addition, inhibition of kainate-evoked GluK2 endocytosis decreased the activation of MLK3-JNK3 signaling and the binding of MLK3-GluK2 in cultured cortical neurons. These results suggest that the internalization of GluK2 following SUMO modification promotes its binding with MLK3, thereby activating the MLK3-JNK3 pathway, which may be responsible for ischemic neuronal cell death.
蛋白质 SUMOylation 参与了缺血性中风的发病机制。然而，其潜在的机制仍不清楚。在这里，我们发现全脑缺血会引起大鼠海马 CA1 区 GluK2 SUMOylation 的持续升高。过表达野生型 GluK2，但不是 SUMOylation 缺陷型突变体，在海人藻酸刺激后显著增加了 MLK3 和 JNK3 的活性。SUMOylation 缺陷减弱了海人藻酸刺激后 MLK3 和 GluK2 之间的相互作用。此外，抑制海人藻酸诱导的 GluK2 内吞作用会降低 MLK3-JNK3 信号通路的激活和培养的皮质神经元中 MLK3-GluK2 的结合。这些结果表明，SUMO 修饰后的 GluK2 内化促进了其与 MLK3 的结合，从而激活了 MLK3-JNK3 通路，这可能是缺血性神经元细胞死亡的原因。
