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Reelin 受体 ApoER2 是衔接蛋白复合物 AP-4 的货物:对遗传性痉挛性截瘫的影响。

The Reelin receptor ApoER2 is a cargo for the adaptor protein complex AP-4: Implications for Hereditary Spastic Paraplegia.

机构信息

Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.

Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

出版信息

Prog Neurobiol. 2024 Mar;234:102575. doi: 10.1016/j.pneurobio.2024.102575. Epub 2024 Jan 26.

DOI:10.1016/j.pneurobio.2024.102575
PMID:38281682
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10979513/
Abstract

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.

摘要

衔接蛋白复合物 4(AP-4)是一种异源四聚体复合物,可促进从反式高尔基体网络中输出选定的货物蛋白。AP-4 亚基中的每个突变都会导致一种复杂形式的遗传性痉挛性截瘫(HSP)。在此,我们报告 Reelin 信号通路中的受体 ApoER2 是 AP-4 复合物的货物。我们确定了 ApoER2 胞质域内的 ISSF/Y 基序是与 AP-4 的经典信号结合口袋相互作用所必需的。AP4E1-KO(敲除)HeLa 细胞和 Ap4e1-KO 小鼠海马神经元显示 ApoER2 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 人类 iPSC 衍生的皮质 i3Neurons 显示 ApoER2 蛋白表达减少。对 ApoER2 的生物合成运输分析表明,该受体的反式高尔基体后运输存在差异,KO 神经元中的轴突分布低于野生型神经元,表明 AP-4 和 ISSF/Y 基序在 ApoER2 的轴突定位中起作用。最后,对小鼠海马和人皮质 KO 神经元中的 Reelin 信号分析表明,AP4 缺乏不会导致 Reelin 依赖性 AKT 途径激活的变化,也不会导致 Reelin 诱导的树突分支发生明显变化,但会降低 Reelin 诱导的 ERK 磷酸化、CREB 激活和高尔基体部署。这项工作因此确立了 ApoER2 为 AP-4 复合物的一种新的货物,表明该受体的运输缺陷以及 Reelin 信号通路的缺陷可能导致由 AP-4 亚基突变引起的 HSP 的发病机制。

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Quantification of Golgi Entry and Exit Kinetics of Protein Cargoes.
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