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

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 interactionsMLK3physically interacts with GluK2 by anti bait coimmunoprecipitation (View Interaction: 1, 2)SUMO1physically interacts with GluK2 by anti bait coimmunoprecipitation (View interaction)MLK3physically interacts with GluK2 by anti bait coimmunoprecipitation (View interaction)

► Transient global brain ischemia increases GluK2 SUMOylation in the vulnerable hippocampal CA1 region.
► GluK2 SUMOylation facilitates the MLK3–JNK3 signaling following kainate stimulation.
► SUMOylation deficiency abolishes the kainate-stimulated interaction between GluK2 and MLK3.
► Internalization of GluK2 following kainate stimuli positively regulates the MLK3–JNK3 signaling and the MLK3–JNK3 binding.
► These data suggest a pathological role of GluK2 SUMOylation in ischemic brain damage.