SUMOylation of the kainate receptor subunit GluK2 contributes to the activation of the MLK3–JNK3 pathway following kainate stimulation

Abstract 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. Structured summary of protein interactions MLK3 physically interacts with GluK2 by anti bait coimmunoprecipitation (View Interaction: 1 , 2 ) SUMO1 physically interacts with GluK2 by anti bait coimmunoprecipitation ( View interaction ) MLK3 physically interacts with GluK2 by anti bait coimmunoprecipitation ( View interaction )