Identification of the Low Density Lipoprotein (LDL) Receptor-related Protein-1 Interactome in Central Nervous System Myelin Suggests a Role in the Clearance of Necrotic Cell Debris
Identification of the Low Density Lipoprotein (LDL) Receptor-related Protein-1 Interactome in Central Nervous System Myelin Suggests a Role in the Clearance of Necrotic Cell Debris
复制标题
DOI：
10.1074/jbc.m112.384693
复制
发表时间：
2013-02-15
影响因子：
4.8
通讯作者：
Gaultier, Alban
中科院分区：
文献类型：
--
作者：
Fernandez-Castaneda, Anthony;Arandjelovic, Sanja;Gaultier, Alban
在中枢神经系统 (CNS) 中，少突胶质细胞产生的髓鞘促进快速神经元信号。少突胶质细胞周转或损伤会产生髓磷脂碎片，通常会被吞噬细胞迅速清除。未能清除垂死的少突胶质细胞会导致降解的髓鞘质的积累，如果被免疫系统识别，可能会导致多发性硬化症等疾病中自身免疫的发展。我们最近发现低密度脂蛋白受体相关蛋白 1 (LRP1) 是一种新型的髓磷脂碎片吞噬受体。在这里，我们报告了中枢神经系统髓磷脂中 LRP1 相互作用组的特征。融合蛋白的设计与 LRP1 的胞外配体结合域相对应。通过亲和纯化分离 LRP1 伴侣并通过质谱进行表征。我们报告说，LRP1 通过其胞外结构域结合胞内蛋白，并作为坏死细胞的受体发挥作用。肽基精氨酸脱亚胺酶-2 和环核苷酸磷酸二酯酶是我们筛选中鉴定的新型 LRP1 配体，它们与全长 LRP1 相互作用。此外，LRP1 的胞外结构域是体外肽基精氨酸脱亚胺酶 2 介导的脱亚胺作用的靶点。我们认为 LRP1 作为细胞损伤和坏死过程中释放的细胞内成分的内吞作用的受体。
In the central nervous system (CNS), fast neuronal signals are facilitated by the oligodendrocyte-produced myelin sheath. Oligodendrocyte turnover or injury generates myelin debris that is usually promptly cleared by phagocytic cells. Failure to remove dying oligodendrocytes leads to accumulation of degraded myelin, which, if recognized by the immune system, may contribute to the development of autoimmunity in diseases such as multiple sclerosis. We recently identified low density lipoprotein receptor-related protein-1 (LRP1) as a novel phagocytic receptor for myelin debris. Here, we report characterization of the LRP1 interactome in CNS myelin. Fusion proteins were designed corresponding to the extracellular ligand-binding domains of LRP1. LRP1 partners were isolated by affinity purification and characterized by mass spectrometry. We report that LRP1 binds intracellular proteins via its extracellular domain and functions as a receptor for necrotic cells. Peptidyl arginine deiminase-2 and cyclic nucleotide phosphodiesterase are novel LRP1 ligands identified in our screen, which interact with full-length LRP1. Furthermore, the extracellular domain of LRP1 is a target of peptidyl arginine deiminase-2-mediated deimination in vitro. We propose that LRP1 functions as a receptor for endocytosis of intracellular components released during cellular damage and necrosis.