E3 ubiquitin ligase Nedd4-2 exerts neuroprotective effects during endoplasmic reticulum stress.
E3 ubiquitin ligase Nedd4-2 exerts neuroprotective effects during endoplasmic reticulum stress.
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DOI：
10.1111/jnc.15567
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发表时间：
2022-03
影响因子：
4.7
通讯作者：
Tsai NP
中科院分区：
文献类型：
--
作者：
Lodes DE;Zhu J;Tsai NP
神经前体细胞表达发育下调蛋白4样（Nedd4-2）是一种E3泛素连接酶，对神经发育和神经回路兴奋性的稳态至关重要。虽然通过多种直接底物泛素化受损，Nedd4-2的失调与癫痫易感性升高有关，但仍不清楚Nedd4-2是否与影响神经元活动和癫痫易感性的其他细胞通路相互连接。在这里，我们首次发现Nedd4-2与内质网（ER）相关，并调节多种内质网驻留蛋白的表达。此外，利用Nedd4-2条件敲除小鼠，我们发现Nedd4-2是维持内质网应激诱导下自发神经活动和兴奋性突触所必需的。在分析内质网应激反应的典型途径激活时，我们发现Nedd4-2是eIF2α磷酸化所必需的。虽然eIF2α的磷酸化已被证明可以降低癫痫易感性，但在Nedd4-2条件敲除小鼠中促进eIF2α磷酸化的尝试未能产生这种有益的功能，这表明Nedd4-2在整合内质网应激反应以调节癫痫易感性方面发挥作用。总之，我们的研究证明了Nedd4-2在神经元内质网应激时的神经保护功能，并可以为Nedd4-2的表达或活性受损的神经系统疾病提供见解。在Nedd4-2条件敲除（cKO）皮质神经元培养中，内质网（ER）应激的诱导导致自发神经活动减少，兴奋性突触减少，真核起始因子-2α (eIF2α)磷酸化受损。在小鼠中，eIF2α磷酸化的损伤加上Nedd4-2缺失导致缺陷，损害了salubrinal介导的癫痫易感性的药理学减少。这些发现揭示了Nedd4-2在神经元内质网应激期间的神经保护功能，并可以深入了解与Nedd4-2活性受损或内质网应激反应改变相关的神经系统疾病。
The neural precursor cell expressed developmentally downregulated protein 4-like (Nedd4-2) is an E3 ubiquitin ligase critical for neurodevelopment and homeostasis of neural circuit excitability. While dysregulation of Nedd4-2 has been linked to elevated seizure susceptibility through impaired ubiquitination of multiple direct substrates, it remains largely unclear whether Nedd4-2 interconnects other cellular pathways that affect neuronal activity and seizure susceptibility. Here, we first showed that Nedd4-2 associates with the endoplasmic reticulum (ER) and regulates the expression of multiple ER resident proteins. Further, utilizing Nedd4-2 conditional knockout mice, we showed that Nedd4-2 is required for the maintenance of spontaneous neural activity and excitatory synapses following the induction of ER stress. When analyzing activation of the canonical pathways of ER stress response, we found that Nedd4-2 is required for phosphorylation of eIF2α. While phosphorylation of eIF2α has been shown to reduce seizure susceptibility, attempts to facilitate phosphorylation of eIF2α in Nedd4-2 conditional knockout mice failed to produce such a beneficial function, suggesting a role for Nedd4-2 in integrating the ER stress response to modulate seizure susceptibility. Altogether, our study demonstrates neuroprotective functions of Nedd4-2 during ER stress in neurons and could provide insight into neurological diseases in which the expression or activity of Nedd4-2 is impaired. In Nedd4-2 conditional knockout (cKO) cortical neuron cultures, induction of endoplasmic reticulum (ER) stress leads to a reduction in spontaneous neural activity, a reduction of excitatory synapses, and impaired eukaryotic initiation factor-2α (eIF2α) phosphorylation. This impairment in eIF2α phosphorylation coupled with Nedd4-2 deletion in mice causes a defect that impairs pharmacological reduction in seizure susceptibility mediated by salubrinal. These findings uncover neuroprotective functions of Nedd4-2 during ER stress in neurons and could provide insight into neurological diseases associated with impaired Nedd4-2 activity or an altered ER stress response.
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