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首页> 外文期刊>Molecular biology of the cell >The adaptor protein GULP promotes Jedi-1-mediated phagocytosis through a clathrin-dependent mechanism
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The adaptor protein GULP promotes Jedi-1-mediated phagocytosis through a clathrin-dependent mechanism

机译:衔接蛋白GULP通过网格蛋白依赖性机制促进Jedi-1介导的吞噬作用

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摘要

During the development of the peripheral nervous system, the large number of apoptotic neurons generated are phagocytosed by glial precursor cells. This clearance is mediated, in part, through the mammalian engulfment receptor Jedi-1. However, the mechanisms by which Jedi-1 mediates phagocytosis are poorly understood. Here we demonstrate that Jedi-1 associates with GULP, the mammalian homologue of CED-6, an adaptor protein required for phagocytosis mediated by the nematode engulfment receptor CED-1. Silencing GULP or mutating the NPXY motif in Jedi-1, which is required for GULP binding, prevents Jedi-1-mediated phagocytosis. How GULP promotes engulfment is not known. Of interest, we find that Jedi-1-induced phagocytosis requires GULP binding to clathrin heavy chain (CHC). During engulfment, CHC is tyrosine phosphorylated, which is required for Jedi-mediated engulfment. Both phosphoclathrin and actin accumulate around engulfed microspheres. Furthermore, knockdown of CHC in HeLa cells prevents Jedi-1-mediated engulfment of microspheres, and knockdown in glial precursors prevents the engulfment of apoptotic neurons. Taken together, these results reveal that Jedi-1 signals through recruitment of GULP, which promotes phagocytosis through a noncanonical phosphoclathrin-dependent mechanism.
机译:在周围神经系统发育过程中,产生的大量凋亡神经元被神经胶质前体细胞吞噬。这种清除是部分通过哺乳动物吞噬受体Jedi-1介导的。但是,对Jedi-1介导吞噬作用的机制了解甚少。在这里,我们证明Jedi-1与GULP(CED-6的哺乳动物同系物)有关,GUED是由线虫吞噬受体CED-1介导的吞噬作用所需的衔接蛋白。沉默GULP或突变Jedi-1中的NPXY基序(这是GULP绑定所必需的),可以防止Jedi-1介导的吞噬作用。 GULP如何促进吞噬尚不清楚。有趣的是,我们发现Jedi-1诱导的吞噬作用需要GULP与网格蛋白重链(CHC)结合。在吞噬过程中,CHC被酪氨酸磷酸化,这是绝地介导的吞噬所必需的。磷clathrin和肌动蛋白都聚集在被吞噬的微球周围。此外,在HeLa细胞中CHC的敲低可防止Jedi-1介导的微球吞噬,而胶质前体的敲低可防止凋亡神经元的吞噬。综上所述,这些结果表明,Jedi-1通过GULP的募集发出信号,GULP通过非规范的磷酸clathrin依赖性机制促进吞噬作用。

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