Seizure protein 6 controls glycosylation and trafficking of kainate receptor subunits GluK2 and GluK3
Seizure protein 6 controls glycosylation and trafficking of kainate receptor subunits GluK2 and GluK3
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DOI：
10.15252/embj.2019103457
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发表时间：
2020-06-22
期刊：
影响因子：
11.4
通讯作者：
Lichtenthaler, Stefan F.
中科院分区：
文献类型：
--
作者：
Pigoni, Martina;Hsia, Hung-En;Lichtenthaler, Stefan F.
癫痫发作蛋白6（SEZ 6）是神经系统发育和维持所必需的，是蛋白酶BACE 1的主要底物，与阿尔茨海默病（AD）和精神疾病有关，但其分子功能尚不清楚。在这里，我们证明，SEZ 6控制糖基化和细胞表面定位的红藻氨酸受体组成的GluK 2/3亚基。SEZ 6的丢失降低了原代神经元中GluK 2/3的表面水平，并降低了急性海马切片中CA 1锥体神经元中红藻氨酸诱发的电流。从机制上讲，SEZ 6在体外和体内的缺失阻止了GluK 2/3与人自然杀伤细胞-1（HNK-1）聚糖（GluK 2/3功能的调节剂）的修饰。SEZ 6通过其胞外结构域与GluK 2相互作用，并在异源细胞和原代神经元的分泌途径中促进GluK 2的内质网后转运。总之，SEZ 6作为GluK 2/3的新的运输因子。这种新功能可能有助于更好地理解SEZ 6在神经和精神疾病中的作用。
Seizure protein 6 (SEZ6) is required for the development and maintenance of the nervous system, is a major substrate of the protease BACE1 and is linked to Alzheimer's disease (AD) and psychiatric disorders, but its molecular functions are not well understood. Here, we demonstrate that SEZ6 controls glycosylation and cell surface localization of kainate receptors composed of GluK2/3 subunits. Loss of SEZ6 reduced surface levels of GluK2/3 in primary neurons and reduced kainate-evoked currents in CA1 pyramidal neurons in acute hippocampal slices. Mechanistically, loss of SEZ6in vitroandin vivoprevented modification of GluK2/3 with the human natural killer-1 (HNK-1) glycan, a modulator of GluK2/3 function. SEZ6 interacted with GluK2 through its ectodomain and promoted post-endoplasmic reticulum transport of GluK2 in the secretory pathway in heterologous cells and primary neurons. Taken together, SEZ6 acts as a new trafficking factor for GluK2/3. This novel function may help to better understand the role of SEZ6 in neurologic and psychiatric diseases.