Department of Neuroscience, College of Physicians and Surgeons, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA.
Cell. 2011 Dec 9;147(6):1369-83. doi: 10.1016/j.cell.2011.09.056.
The cytoplasmic polyadenylation element-binding protein 3 (CPEB3), a regulator of local protein synthesis, is the mouse homolog of ApCPEB, a functional prion protein in Aplysia. Here, we provide evidence that CPEB3 is activated by Neuralized1, an E3 ubiquitin ligase. In hippocampal cultures, CPEB3 activated by Neuralized1-mediated ubiquitination leads both to the growth of new dendritic spines and to an increase of the GluA1 and GluA2 subunits of AMPA receptors, two CPEB3 targets essential for synaptic plasticity. Conditional overexpression of Neuralized1 similarly increases GluA1 and GluA2 and the number of spines and functional synapses in the hippocampus and is reflected in enhanced hippocampal-dependent memory and synaptic plasticity. By contrast, inhibition of Neuralized1 reduces GluA1 and GluA2 levels and impairs hippocampal-dependent memory and synaptic plasticity. These results suggest a model whereby Neuralized1-dependent ubiquitination facilitates hippocampal plasticity and hippocampal-dependent memory storage by modulating the activity of CPEB3 and CPEB3-dependent protein synthesis and synapse formation.
细胞质多聚腺苷酸化元件结合蛋白 3（CPEB3）是一种局部蛋白合成的调节剂，是 Aplysia 中功能性朊病毒蛋白 ApCPEB 的小鼠同源物。在这里，我们提供的证据表明，神经调节素 1（Neuralized1），一种 E3 泛素连接酶，可激活 CPEB3。在海马培养物中，Neuralized1 介导的 CPEB3 泛素化激活可导致新的树突棘生长，并增加 AMPA 受体的 GluA1 和 GluA2 亚基，这是突触可塑性所必需的两个 CPEB3 靶标。条件性过表达 Neuralized1 同样增加了 GluA1 和 GluA2 的数量以及棘突和功能突触的数量，并反映在增强的海马依赖性记忆和突触可塑性中。相比之下，抑制 Neuralized1 会降低 GluA1 和 GluA2 水平，并损害海马依赖性记忆和突触可塑性。这些结果表明，Neuralized1 依赖性泛素化通过调节 CPEB3 和 CPEB3 依赖性蛋白合成和突触形成来促进海马可塑性和海马依赖性记忆存储的模型。
