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

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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.