神经元活动通过结合eIF4G2:uORF快速重编程树突翻译，这一成果由美国洛克菲勒大学Robert B. Darnell、Ezgi Hacisuleyman和麻省理工学院Jonathan S. Weissman课题组合作取得。2024年4月8日出版的《自然-神经科学》杂志发表了这项成果。

在这项研究中，为了监测去极化如何影响局部树突生物学，研究人员采用了树突靶向接近标记方法，进行交联免疫沉淀、核糖体分析和质谱分析。用氯化钾或谷氨酸激动剂DHPG对原发性皮层神经元进行去极化，会导致树突蛋白表达的快速重编程，其中树突mRNA和蛋白的变化相关性较弱。

对于预定位信息的一个子集，去极化增加了上游开放阅读框（uORF）及其下游编码序列的翻译，使长期电位、细胞信号传导和能量代谢的蛋白质得以定位生产。这种依赖于活性的翻译伴随着非典型翻译起始因子eIF4G2的磷酸化和招募，翻译的uORFs足以赋予去极化诱导的、依赖于eIF4G2的翻译调控。这些研究揭示了一种特殊的机制，即eIF4G2依赖的活性uORF翻译控制将活性与局部树突重塑联系起来。

据悉，学习和记忆需要活动诱导的树突翻译变化，但还不清楚哪些mRNA参与到该过程以及它们受怎样的调控。

附：英文原文

Title: Neuronal activity rapidly reprograms dendritic translation via eIF4G2:uORF binding

Author: Hacisuleyman, Ezgi, Hale, Caryn R., Noble, Natalie, Luo, Ji-dung, Fak, John J., Saito, Misa, Chen, Jin, Weissman, Jonathan S., Darnell, Robert B.

Issue&Volume: 2024-04-08

Abstract: Learning and memory require activity-induced changes in dendritic translation, but which mRNAs are involved and how they are regulated are unclear. In this study, to monitor how depolarization impacts local dendritic biology, we employed a dendritically targeted proximity labeling approach followed by crosslinking immunoprecipitation, ribosome profiling and mass spectrometry. Depolarization of primary cortical neurons with KCl or the glutamate agonist DHPG caused rapid reprogramming of dendritic protein expression, where changes in dendritic mRNAs and proteins are weakly correlated. For a subset of pre-localized messages, depolarization increased the translation of upstream open reading frames (uORFs) and their downstream coding sequences, enabling localized production of proteins involved in long-term potentiation, cell signaling and energy metabolism. This activity-dependent translation was accompanied by the phosphorylation and recruitment of the non-canonical translation initiation factor eIF4G2, and the translated uORFs were sufficient to confer depolarization-induced, eIF4G2-dependent translational control. These studies uncovered an unanticipated mechanism by which activity-dependent uORF translational control by eIF4G2 couples activity to local dendritic remodeling.

DOI: 10.1038/s41593-024-01615-5

Source: https://www.nature.com/articles/s41593-024-01615-5