Department of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chunchon, 24252, South Korea.
Cell Death Dis. 2019 Jul 18;10(8):545. doi: 10.1038/s41419-019-1781-0.
Neuronal precursor cell expressed developmentally downregulated 4-2 (NEDD4-2) is an E3 ubiquitin ligase to regulate ion transport by controlling cellular trafficking/endocytosis and lysosomal degradation of ion channels and transporters. Thus, NEDD4-2 is relevant to neuronal excitability and epileptic encephalopathies in human patients. However, the regulatory molecules for NEDD4-2 dephosphorylation have been still elusive. Here, we demonstrate that pyridoxal-5'-phosphate phosphatase/chronophin (PLPP/CIN) specifically dephosphorylated NEDD4-2 serine (S) 448 site. PLPP/CIN deletion inhibited NEDD4-2 ubiquitination, and diminished the responsiveness of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) by facilitating NEDD4-2-mediated ubiquitination of GluA1 subunit under physiological condition. PLPP/CIN overexpression reversed these effects. These PLPP/CIN-mediated processes were required for the increased seizure severity and its progression in response to kainic acid (KA). Therefore, we suggest the novel function of PLPP/CIN as a NEDD4-2 phosphatase, which may be a potential therapeutic target for NEDD4-2-associated diseases as well as various neurological and psychiatric disorders, including epilepsy.
神经元前体细胞表达的发育下调蛋白 4-2（NEDD4-2）是一种 E3 泛素连接酶，通过控制离子通道和转运蛋白的细胞转运/内吞作用和溶酶体降解来调节离子转运。因此，NEDD4-2 与人类患者的神经元兴奋性和癫痫性脑病有关。然而，NEDD4-2 去磷酸化的调节分子仍然难以捉摸。在这里，我们证明了吡哆醛-5'-磷酸磷酸酶/chronophin（PLPP/CIN）特异性地去磷酸化 NEDD4-2 丝氨酸（S）448 位。PLPP/CIN 缺失抑制了 NEDD4-2 的泛素化，并且在生理条件下促进了 NEDD4-2 介导的 GluA1 亚基的泛素化，从而降低了 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的反应性。PLPP/CIN 的过表达逆转了这些效应。PLPP/CIN 介导的这些过程对于响应海人酸（KA）时增加的癫痫发作严重程度及其进展是必需的。因此，我们提出了 PLPP/CIN 作为 NEDD4-2 磷酸酶的新功能，它可能是与 NEDD4-2 相关疾病以及各种神经和精神疾病（包括癫痫）的潜在治疗靶点。
