Mechanism of secretory cargo sorting at the trans Golgi Network (TGN) and its relevance in vivo

新合成的货物从内质网(ER)进入高尔基体，穿过高尔基体，在跨高尔基体网络(TGN)被分拣，通过特定的运输载体运输到各自的细胞部分或分泌。根据细胞类型的不同，这些新合成的转运载体的目的地包括：顶端和基底外侧细胞表面、早期/分选内小体、晚期内小体、循环内小体、分泌储存颗粒、前高尔基体池和内质网。各自的货物是如何分类的？到目前为止，溶酶体水解酶的分选是TGN中所有分选事件中最具特点的。这些蛋白与甘露糖-6-磷酸受体(M6PR)结合，并通过笼蛋白包裹的小泡运输到溶酶体。去往细胞表面的完整膜蛋白已知在它们的细胞质尾部含有输出信号，但到目前为止还没有出现它们从TGN输出的一般规则。除了MP6R，到目前为止还没有发现用于可溶性分泌性货物分选的货物受体。这些分子是如何被分拣和包装到TGN的萌芽运输载体中的？最近，我们在TGN上描述了一种新的分选机制，包括肌动蛋白、肌动蛋白切割蛋白ADF/cofilin、分泌途径ATPase 1(SPCA1)和钙离子。我未来工作的主要目标是剖析这一过程的机制，并最终了解这些分泌蛋白在TGN是如何分类的。这将通过在体外和体内定义参与这一过程的新成分来实现。

Newly synthesized cargo arrives from the endoplasmic reticulum (ER) into the Golgi, travels across the Golgi, and is sorted at the Trans Golgi Network (TGN) for transport to respective cellular compart-ments or for secretion, by specific transport carriers. These destinations, for the newly synthesized transport carriers include, depending on the cell type: apical and basolateral cell surface, early/sorting endosomes, late endosomes, recycling endosomes, secretory storage granules, preceding Golgi cisternae, and the ER. How are the respective cargoes sorted? The sorting of lysosomal hydrolases is by far the best characterized of all the sorting events in the TGN. These proteins bind to the mannose-6-phosphate receptor (M6PR) and are transported to the lysosome by clathrin-coated vesicles. Integral membrane proteins destined to the cell surface are known to contain export signals in their cytoplasmic tails, but no general rule has emerged thus far for their export from the TGN. Apart from the MP6R no cargo receptors have until now been identified for the sorting of soluble secretory cargo. How such molecules are sorted and packed into the budding transport carriers at the TGN? Recently, we described a new sorting mechanism at the TGN that includes actin, the actin severing proteins ADF/cofilin, the secretory pathway ATPase 1 (SPCA1) and Ca2+. The major aim of my future work is to dissect the mechanism of this process and finally to understand how these secretory proteins are sorted at the TGN. This will be achieved by defining new components involved in the process in vitro and in vivo.