Aagab acts as a novel regulator of NEDD4-1-mediated Pten nuclear translocation to promote neurological recovery following hypoxic-ischemic brain damage
Aagab acts as a novel regulator of NEDD4-1-mediated Pten nuclear translocation to promote neurological recovery following hypoxic-ischemic brain damage
复制标题
Aagab 作为 NEDD4-1 介导的 Pten 核转位的新型调节剂，促进缺氧缺血性脑损伤后的神经功能恢复
DOI：
10.1038/s41418-021-00757-4
复制
发表时间：
2021-03-12
影响因子：
12.4
通讯作者：
Dong, Zhifang
中科院分区：
文献类型：
--
作者：
Dai, Chunfang;Wu, Bin;Dong, Zhifang
缺氧缺血性脑病（HIE）是围产期和新生儿期死亡和严重神经功能缺损的主要原因。然而，令人满意的治疗策略却很少。在这里，我们报道了一个快速核转位的磷酸酶和张力蛋白同源物删除的染色体上TEN（PTEN）是一个重要的步骤，在缺氧缺血性脑损伤（HIBD）和氧-葡萄糖剥夺（OGD）诱导的神经元损伤在体内和体外。此外，我们发现OGD诱导的PTEN核转位依赖于由神经前体细胞表达的发育下调蛋白4-1（NEDD 4 -1）介导的PTEN在赖氨酸13残基（K13）处的单泛素化。重要的是，我们首次鉴定了α-和γ-适应素结合蛋白（Aagab）作为一种新的NEDD 4 -1调节剂，以调节NEDD 4 -1的水平，随后介导Pten核转位。最后，我们证明了基因上调Aagab或应用Tat-K13肽（一种位于PTEN K13残基侧翼的短干扰肽）不仅减少了Pten核转位，而且显著减轻了HIBD模型大鼠的肌力、运动和空间学习记忆障碍。提示Aagab可能通过调节NEDD 4 -1介导的Pten核转位促进新生大鼠HIBD后的功能恢复，为临床治疗HIE提供新的治疗靶点。
Hypoxic-ischemic encephalopathy (HIE) is a main cause of mortality and severe neurologic impairment in the perinatal and neonatal period. However, few satisfactory therapeutic strategies are available. Here, we reported that a rapid nuclear translocation of phosphatase and tensin homolog deleted on chromosome TEN (PTEN) is an essential step in hypoxic-ischemic brain damage (HIBD)- and oxygen-glucose deprivation (OGD)-induced neuronal injures both in vivo and in vitro. In addition, we found that OGD-induced nuclear translocation of PTEN is dependent on PTEN mono-ubiquitination at the lysine 13 residue (K13) that is mediated by neural precursor cell expressed developmentally downregulated protein 4-1 (NEDD4-1). Importantly, we for the first time identified alpha- and gamma-adaptin binding protein (Aagab) as a novel NEDD4-1 regulator to regulate the level of NEDD4-1, subsequently mediating Pten nuclear translocation. Finally, we demonstrated that genetic upregulation of Aagab or application of Tat-K13 peptide (a short interference peptide that flanks K13 residue of PTEN) not only reduced Pten nuclear translocation, but also significantly alleviated the deficits of myodynamia, motor and spatial learning and memory in HIBD model rats. These results suggest that Aagab may serve as a regulator of NEDD4-1-mediated Pten nuclear translocation to promote functional recovery following HIBD in neonatal rats, and provide a new potential therapeutic target to guide the clinical treatment for HIE.