解密HuD介导的神经元分化过程中Akt1与HuD的相互作用

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Hikari Nishisaka , Takumi Tomohiro , Kako Fukuzumi, Akira Fukao, Yoshinori Funakami, Toshinobu Fujiwara
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引用次数: 0

摘要

RNA 结合蛋白 HuD/ELAVL4 通过调控目标 mRNA 的各种转录后过程,包括稳定性、翻译和定位,对神经元发育和突触可塑性至关重要。我们以前的研究表明,HuD 的连接区和聚(A)结合域在促进翻译和诱导神经元生长方面起着关键作用。此外,我们还发现 HuD 只通过连接区与活性形式的 Akt1 相互作用。虽然这种相互作用对神经元的生长至关重要,但 HuD 并不是 Akt1 的底物,这就引起了关于 HuD 介导的翻译刺激与其与活性 Akt1 之间的动态关联的问题。我们确定了HuD连接区中负责与Akt1相互作用的关键氨基酸,从而产生了两种点突变的HuD变体:一种不能与Akt1结合,另一种无论其磷酸化状态如何都能与Akt1相互作用。使用这些突变体进行的体外翻译试验表明,HuD 介导的翻译刺激与它与 Akt1 的结合无关。此外,HuD 与活性 Akt1 之间的相互作用显然对于 HuD 诱导的神经元生长至关重要,而能够与任何形式的 Akt1 结合的 HuD 突变体则会导致神经元发育异常。总之,我们的研究结果重新审视了对 HuD-Akt1 在翻译中相互作用的理解,并表明这种相互作用通过一种不同于翻译调控的独特分子机制促进了 HuD 介导的神经元生长。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Deciphering the Akt1-HuD interaction in HuD-mediated neuronal differentiation

The RNA-binding protein HuD/ELAVL4 is essential for neuronal development and synaptic plasticity by governing various post-transcriptional processes of target mRNAs, including stability, translation, and localization. We previously showed that the linker region and poly(A)-binding domain of HuD play a pivotal role in promoting translation and inducing neurite outgrowth. In addition, we found that HuD interacts exclusively with the active form of Akt1, through the linker region. Although this interaction is essential for neurite outgrowth, HuD is not a substrate for Akt1, raising questions about the dynamics between HuD-mediated translational stimulation and its association with active Akt1.

Here, we demonstrate that active Akt1 interacts with the cap-binding complex via HuD. We identify key amino acids in linker region of HuD responsible for Akt1 interaction, leading to the generation of two point-mutated HuD variants: one that is incapable of binding to Akt1 and another that can interact with Akt1 regardless of its phosphorylation status. In vitro translation assays using these mutants reveal that HuD-mediated translation stimulation is independent of its binding to Akt1. In addition, it is evident that the interaction between HuD and active Akt1 is essential for HuD-induced neurite outgrowth, whereas a HuD mutant capable of binding to any form of Akt1 leads to aberrant neurite development.

Collectively, our results revisit the understanding of the HuD-Akt1 interaction in translation and suggest that this interaction contributes to HuD-mediated neurite outgrowth via a unique molecular mechanism distinct from translation regulation.

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来源期刊
Biochimie
Biochimie 生物-生化与分子生物学
CiteScore
7.20
自引率
2.60%
发文量
219
审稿时长
40 days
期刊介绍: Biochimie publishes original research articles, short communications, review articles, graphical reviews, mini-reviews, and hypotheses in the broad areas of biology, including biochemistry, enzymology, molecular and cell biology, metabolic regulation, genetics, immunology, microbiology, structural biology, genomics, proteomics, and molecular mechanisms of disease. Biochimie publishes exclusively in English. Articles are subject to peer review, and must satisfy the requirements of originality, high scientific integrity and general interest to a broad range of readers. Submissions that are judged to be of sound scientific and technical quality but do not fully satisfy the requirements for publication in Biochimie may benefit from a transfer service to a more suitable journal within the same subject area.
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