Reelin受体ApoER2是适应蛋白复合物AP-4的载体:对遗传性痉挛性截瘫的影响

IF 6.7 2区 医学 Q1 NEUROSCIENCES Progress in Neurobiology Pub Date : 2024-01-26 DOI:10.1016/j.pneurobio.2024.102575
Mario O. Caracci , Héctor Pizarro , Carlos Alarcón-Godoy , Luz M. Fuentealba , Pamela Farfán , Raffaella De Pace , Natacha Santibañez , Viviana A. Cavieres , Tammy P. Pástor , Juan S. Bonifacino , Gonzalo A. Mardones , María-Paz Marzolo
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引用次数: 0

摘要

适应蛋白复合物 4(AP-4)是一种异源四聚体复合物,能促进选定的货物蛋白从跨高尔基体网络中输出。AP-4 各亚基的突变会导致一种复杂的遗传性痉挛性截瘫(HSP)。在本文中,我们报告了 ApoER2(一种 Reelin 信号通路中的受体)是 AP-4 复合物的载货。我们发现 ApoER2 细胞质结构域中的 ISSF/Y 矩阵是与 AP-4 的 µ4 (AP4M1) 亚基的典型信号结合袋相互作用的必要条件。AP4E1- 敲除(KO)的 HeLa 细胞和 Ap4e1-KO 小鼠的海马神经元显示载脂蛋白 E2 与高尔基体标记物的共定位增加。此外,Ap4e1-KO 小鼠的海马神经元和 AP4M1-KO 人 iPSC 衍生的皮质 i3Neurons 的 ApoER2 蛋白表达量减少。对 ApoER2 生物合成运输的分析表明,该受体在高尔基体后的运输存在差异,与野生型神经元相比,KO 神经元的轴突分布较少,这表明 AP-4 和 ISSF/Y motif 在 ApoER2 的轴突定位中发挥作用。最后,对小鼠海马和人类皮质 KO 神经元中的胰岛素信号转导的分析表明,AP4 的缺乏不会导致胰岛素依赖的 AKT 通路激活发生变化,也只会导致胰岛素诱导的树突轴化发生轻微变化,但会降低胰岛素诱导的 ERK 磷酸化、CREB 激活和高尔基体的部署。因此,这项研究将 ApoER2 确立为 AP-4 复合物的一种新型载体,表明这种受体的贩运和 Reelin 信号转导途径的缺陷可能是 AP-4 亚基突变导致 HSP 发病的原因之一。
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The Reelin receptor ApoER2 is a cargo for the adaptor protein complex AP-4: Implications for Hereditary Spastic Paraplegia

Adaptor protein complex 4 (AP-4) is a heterotetrameric complex that promotes export of selected cargo proteins from the trans-Golgi network. Mutations in each of the AP-4 subunits cause a complicated form of Hereditary Spastic Paraplegia (HSP). Herein, we report that ApoER2, a receptor in the Reelin signaling pathway, is a cargo of the AP-4 complex. We identify the motif ISSF/Y within the ApoER2 cytosolic domain as necessary for interaction with the canonical signal-binding pocket of the µ4 (AP4M1) subunit of AP-4. AP4E1- knock-out (KO) HeLa cells and hippocampal neurons from Ap4e1-KO mice display increased co-localization of ApoER2 with Golgi markers. Furthermore, hippocampal neurons from Ap4e1-KO mice and AP4M1-KO human iPSC-derived cortical i3Neurons exhibit reduced ApoER2 protein expression. Analyses of biosynthetic transport of ApoER2 reveal differential post-Golgi trafficking of the receptor, with lower axonal distribution in KO compared to wild-type neurons, indicating a role of AP-4 and the ISSF/Y motif in the axonal localization of ApoER2. Finally, analyses of Reelin signaling in mouse hippocampal and human cortical KO neurons show that AP4 deficiency causes no changes in Reelin-dependent activation of the AKT pathway and only mild changes in Reelin-induced dendritic arborization, but reduces Reelin-induced ERK phosphorylation, CREB activation, and Golgi deployment. This work thus establishes ApoER2 as a novel cargo of the AP-4 complex, suggesting that defects in the trafficking of this receptor and in the Reelin signaling pathway could contribute to the pathogenesis of HSP caused by mutations in AP-4 subunits.

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来源期刊
Progress in Neurobiology
Progress in Neurobiology 医学-神经科学
CiteScore
12.80
自引率
1.50%
发文量
107
审稿时长
33 days
期刊介绍: Progress in Neurobiology is an international journal that publishes groundbreaking original research, comprehensive review articles and opinion pieces written by leading researchers. The journal welcomes contributions from the broad field of neuroscience that apply neurophysiological, biochemical, pharmacological, molecular biological, anatomical, computational and behavioral analyses to problems of molecular, cellular, developmental, systems, and clinical neuroscience.
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