Laboratory of Developmental Genetics, The Rockefeller University, New York, NY, USA.
Developmental Biology Program, Sloan Kettering Institute, New York, NY, USA.
Nat Cell Biol. 2018 Apr;20(4):393-399. doi: 10.1038/s41556-018-0068-5. Epub 2018 Mar 19.
Phagocytosis of dying cells is critical in development and immunity. Although proteins for recognition and engulfment of cellular debris following cell death are known, proteins that directly mediate phagosome sealing are uncharacterized. Furthermore, whether all phagocytic targets are cleared using the same machinery is unclear. Degeneration of morphologically complex cells, such as neurons, glia and melanocytes, produces phagocytic targets of various shapes and sizes located in different microenvironments. Thus, such cells offer unique settings to explore engulfment programme mechanisms and specificity. Here, we report that dismantling and clearance of a morphologically complex Caenorhabditis elegans epithelial cell requires separate cell soma, proximal and distal process programmes. Similar compartment-specific events govern the elimination of a C. elegans neuron. Although canonical engulfment proteins drive cell soma clearance, these are not required for process removal. We find that EFF-1, a protein previously implicated in cell-cell fusion , specifically promotes distal process phagocytosis. EFF-1 localizes to phagocyte pseudopod tips and acts exoplasmically to drive phagosome sealing. eff-1 mutations result in phagocytosis arrest with unsealed phagosomes. Our studies suggest universal mechanisms for dismantling morphologically complex cells and uncover a phagosome-sealing component that promotes cell process clearance.
吞噬凋亡细胞对于发育和免疫至关重要。尽管已知有识别和吞噬细胞死亡后细胞碎片的蛋白质，但直接介导吞噬体封闭的蛋白质尚未被描述。此外，所有吞噬作用的靶标是否都使用相同的机制被清除尚不清楚。形态复杂的细胞（如神经元、神经胶质细胞和黑色素细胞）的变性产生了各种形状和大小的吞噬作用靶标，位于不同的微环境中。因此，这些细胞提供了独特的环境来探索吞噬作用程序的机制和特异性。在这里，我们报告说，形态复杂的秀丽隐杆线虫上皮细胞的解体和清除需要单独的细胞体、近端和远端过程程序。类似的特定于隔室的事件控制着秀丽隐杆线虫神经元的消除。虽然经典的吞噬蛋白驱动细胞体的清除，但这对于过程的去除不是必需的。我们发现，EFF-1，一种先前被认为参与细胞-细胞融合的蛋白质 ，特异性地促进远端过程的吞噬作用。EFF-1 定位于吞噬细胞伪足尖端，并在细胞外发挥作用，驱动吞噬体封闭。eff-1 突变导致吞噬作用停滞，吞噬体未封闭。我们的研究表明了形态复杂的细胞解体的通用机制，并揭示了一种促进细胞过程清除的吞噬体封闭成分。
