Three sorting nexins drive the degradation of apoptotic cells in response to PtdIns(3)P signaling.
Three sorting nexins drive the degradation of apoptotic cells in response to PtdIns(3)P signaling.
复制标题
DOI：
10.1091/mbc.e10-09-0756
复制
发表时间：
2011-02-01
影响因子：
3.3
通讯作者：
Zhou Z
中科院分区：
文献类型：
--
作者：
Lu N;Shen Q;Mahoney TR;Liu X;Zhou Z
在秀丽线虫的发育过程中，LST-4/SNX9、SNX-1和SNX-6作为PtdIns(3)P效应因子共同促进了凋亡细胞的降解。这三种分类连接素通过诱导局部膜弯曲和维持吞噬小体上的RAB-7 GTP酶，刺激内吞细胞器与吞噬小体的融合。凋亡细胞迅速被吞噬细胞吞噬，并在吞噬小体内降解。吞噬小体的成熟需要磷脂酰肌醇3-磷酸[PtdIns(3)P]，然而PtdIns(3)P是如何触发吞噬小体成熟的还很大程度上还不清楚。通过线虫全基因组的PtdIns(3)P效应筛选，我们鉴定了LST-4/SNX9、SNX-1和SNX-6这三个含有bar结构域的分选连接蛋白，它们以两条平行的途径作用于PtdIns(3)P介导的细胞凋亡的降解。我们发现，这些蛋白通过与PtdIns(3)P结合和通过特定的蛋白质-蛋白质相互作用在吞噬体表面得到丰富，它们促进了早期内小体和溶酶体与吞噬小体的融合，这是吞噬小体成熟所必需的事件。具体地说，LST-4与一个重要的吞噬小体成熟启动子Dyn-1(Dynamin)相互作用，以加强Dyn-1‘S与吞噬小体表面的结合，并促进吞噬小体表面RAB-7 GTP酶的维持。此外，LST-4和SNX-1都促进吞噬小管的延长，以促进细胞内小泡的对接和融合。我们的发现确定了两组分类连接蛋白在吞噬小体成熟过程中的关键和不同功能，并揭示了吞噬细胞受体CED-1启动、PtdIns(3)P介导的信号级联反应，并通过这些分类连接蛋白降解凋亡细胞。
LST-4/SNX9, SNX-1, and SNX-6 together drive the degradation of apoptotic cells, as PtdIns(3)P effectors, during Caenorhabditis elegans development. By inducing regional membrane curvature and maintaining RAB-7 GTPase on phagosomes, these three sorting nexins stimulate the fusion of endocytic organelles with phagosomes. Apoptotic cells are swiftly engulfed by phagocytes and degraded inside phagosomes. Phagosome maturation requires phosphatidylinositol 3-phosphate [PtdIns(3)P], yet how PtdIns(3)P triggers phagosome maturation remains largely unknown. Through a genome-wide PtdIns(3)P effector screen in the nematode Caenorhabditis elegans, we identified LST-4/SNX9, SNX-1, and SNX-6, three BAR domain-containing sorting nexins, that act in two parallel pathways to drive PtdIns(3)P-mediated degradation of apoptotic cells. We found that these proteins were enriched on phagosomal surfaces through association with PtdIns(3)P and through specific protein–protein interaction, and they promoted the fusion of early endosomes and lysosomes to phagosomes, events essential for phagosome maturation. Specifically, LST-4 interacts with DYN-1 (dynamin), an essential phagosome maturation initiator, to strengthen DYN-1’s association to phagosomal surfaces, and facilitates the maintenance of the RAB-7 GTPase on phagosomal surfaces. Furthermore, both LST-4 and SNX-1 promote the extension of phagosomal tubules to facilitate the docking and fusion of intracellular vesicles. Our findings identify the critical and differential functions of two groups of sorting nexins in phagosome maturation and reveal a signaling cascade initiated by phagocytic receptor CED-1, mediated by PtdIns(3)P, and executed through these sorting nexins to degrade apoptotic cells.