Martin Stéphane, Nishimune Atsushi, Mellor Jack R, Henley Jeremy M
MRC Centre for Synaptic Plasticity, Anatomy Department, University Walk, University of Bristol, Bristol, BS8 1TD, UK.
Nature. 2007 May 17;447(7142):321-5. doi: 10.1038/nature05736. Epub 2007 May 7.
The small ubiquitin-like modifier protein (SUMO) regulates transcriptional activity and the translocation of proteins across the nuclear membrane. The identification of SUMO substrates outside the nucleus is progressing but little is yet known about the wider cellular role of protein SUMOylation. Here we report that in rat hippocampal neurons multiple SUMOylation targets are present at synapses and we show that the kainate receptor subunit GluR6 is a SUMO substrate. SUMOylation of GluR6 regulates endocytosis of the kainate receptor and modifies synaptic transmission. GluR6 exhibits low levels of SUMOylation under resting conditions and is rapidly SUMOylated in response to a kainate but not an N-methyl-D-aspartate (NMDA) treatment. Reducing GluR6 SUMOylation using the SUMO-specific isopeptidase SENP-1 prevents kainate-evoked endocytosis of the kainate receptor. Furthermore, a mutated non-SUMOylatable form of GluR6 is not endocytosed in response to kainate in COS-7 cells. Consistent with this, electrophysiological recordings in hippocampal slices demonstrate that kainate-receptor-mediated excitatory postsynaptic currents are decreased by SUMOylation and enhanced by deSUMOylation. These data reveal a previously unsuspected role for SUMO in the regulation of synaptic function.
小泛素样修饰蛋白（SUMO）可调节转录活性以及蛋白质跨核膜的转运。细胞核外SUMO底物的鉴定工作正在推进，但对于蛋白质SUMO化在更广泛细胞功能中的作用仍知之甚少。在此，我们报告在大鼠海马神经元中，多个SUMO化靶点存在于突触处，并且我们发现红藻氨酸受体亚基GluR6是一种SUMO底物。GluR6的SUMO化调节红藻氨酸受体的内吞作用并改变突触传递。GluR6在静息条件下SUMO化水平较低，在受到红藻氨酸而非N-甲基-D-天冬氨酸（NMDA）处理时会迅速发生SUMO化。使用SUMO特异性异肽酶SENP-1降低GluR6的SUMO化可阻止红藻氨酸诱发的红藻氨酸受体内吞作用。此外，在COS-7细胞中，一种突变的不可SUMO化形式的GluR6不会因红藻氨酸而发生内吞。与此一致的是，海马脑片的电生理记录表明，SUMO化会降低红藻氨酸受体介导的兴奋性突触后电流，而去SUMO化则会增强该电流。这些数据揭示了SUMO在调节突触功能方面此前未被怀疑的作用。
