Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Tissue Regeneration, Repair and Restoration, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304, USA.
Neuron. 2013 Sep 4;79(5):873-86. doi: 10.1016/j.neuron.2013.06.046.
Phagocytosis controls CNS homeostasis by facilitating the removal of unwanted cellular debris. Accordingly, impairments in different receptors or proteins involved in phagocytosis result in enhanced inflammation and neurodegeneration. While various studies have identified extrinsic factors that modulate phagocytosis in health and disease, key intracellular regulators are less understood. Here we show that the autophagy protein beclin 1 is required for efficient phagocytosis in vitro and in mouse brains. Furthermore, we show that beclin 1-mediated impairments in phagocytosis are associated with dysfunctional recruitment of retromer to phagosomal membranes, reduced retromer levels, and impaired recycling of phagocytic receptors CD36 and Trem2. Interestingly, microglia isolated from human Alzheimer's disease (AD) brains show significantly reduced beclin 1 and retromer protein levels. These findings position beclin 1 as a link between autophagy, retromer trafficking, and receptor-mediated phagocytosis and provide insight into mechanisms by which phagocytosis is regulated and how it may become impaired in AD.
吞噬作用通过促进清除不需要的细胞碎片来控制中枢神经系统的稳态。因此，不同受体或参与吞噬作用的蛋白质的损伤会导致炎症和神经退行性变增强。虽然许多研究已经确定了调节吞噬作用的外在因素，但关键的细胞内调节因子了解较少。在这里，我们表明自噬蛋白 beclin 1 是体外和在小鼠大脑中有效吞噬作用所必需的。此外，我们表明，beclin 1 介导的吞噬作用受损与 retromer 向吞噬体膜的功能失调募集、retromer 水平降低以及吞噬受体 CD36 和 Trem2 的回收受损有关。有趣的是，从小脑淀粉样血管病（AD）患者大脑中分离出的小胶质细胞显示 beclin 1 和 retromer 蛋白水平显著降低。这些发现将 beclin 1 定位为自噬、retromer 运输和受体介导的吞噬作用之间的联系，并深入了解吞噬作用如何被调节以及它如何在 AD 中受损。
