细胞内运输依赖于动力蛋白与其货物之间相互作用的精确调控。我们的研究发现，SNX6作为retromer运输蛋白复合体亚基，参与逆向运输动力蛋白dynein-dynactin对囊泡货物的识别和卸载。SNX1能感知膜曲度并募集SNX6到货物富集的胞内体膜上。SNX6通过结合dynactin亚基p150Glued将动力蛋白连接到胞内体并促进形成运输囊泡。当运输囊泡到达反式高尔基体膜时，高尔基体膜富含的磷脂分子PI(4)P通过抑制SNX6和p150Glued的相互作用，促使运输囊泡和动力蛋白解离，从而使囊泡货物精确释放于靶膜上。这些发现提示生物膜的生化及物理属性对动力蛋白-货物相互作用具有调控作用。我们计划运用生物化学和细胞生物学方法，用蛋白质-脂质体结合检测体系及活细胞成像技术，检测磷脂及膜曲度对于SNX1-SNX6-p150Glued运输复合体的组装和去组装的调控作用，解析货物卸载时运输复合体的

Intracellular transport relies upon precise spatiotemporal control of motor-cargo interaction. Previously we showed that SNX6, a subunit of the retromer protein complex, plays important roles in the recognition and release of vesicular cargoes by the molecular motor dynein-dynactin. During retromer-mediated retrograde transport from endosomes to trans-Golgi network (TGN), SNX1 senses membrane curvature and recruits SNX6 to cargo-enriched endosomal membrane. SNX6 tethers the motor to endosomes through its direct interaction with dynactin p150Glued and facilitates formation and detachment of transport vesicles from endosomal membrane. When transport vesicles reach the TGN, Golgi-enriched PI(4)P facilitates dissociation of the motor from vesicular cargo via inhibition of the interaction between SNX6 and p150Glued, thus providing a molecular mechanism for cargo release at the target membrane. These findings suggest that the biochemical and physical properties of the endomembrane system play critical roles in regulatory mechanisms for motor-cargo interaction. In order to further investigate molecular mechanisms for the spatial and temporal control of retrograde vesicular transport, we propose to employ in vitro assay systems for protein-liposome binding in combination with live cell imaging to 1) investigate impacts of phospholipids and membrane curvature on the assembly and disassembly of the SNX1-SNX6-p150Glued transport complex; 2) monitor the fate of the transport complex once the transport vesicles arrive at the target membrane.