Biogenesis of Dense-Core Secretory Granules

Dense core granules (DCGs) are vesicular organelles derived from outbound traffic through the eukaryotic secretory pathway. As DCGs are formed, the secretory pathway can also give rise to other types of vesicles, such as those bound for endosomes, lysosomes, and the cell surface. DCGs differ from these other vesicular carriers in both content and function, storing highly concentrated cores’ of condensed cargo in vesicles that are stably maintained within the cell until a specific extracellular stimulus causes their fusion with the plasma membrane. These unique features are imparted by the activities of membrane and lumenal proteins that are specifically delivered to the vesicles during synthesis. This chapter will describe the DCG biogenesis pathway, beginning with the sorting of DCG proteins from proteins that are destined for other types of vesicle carriers. In the trans-Golgi network (TGN), sorting occurs as DCG proteins aggregate, causing physical separation from non-DCG proteins. Recent work addresses the nature of interactions that produce these aggregates, as well as potentially important interactions with membranes and membrane proteins. DCG proteins are released from the TGN in vesicles called immature secretory granules (ISGs). The mechanism of ISG formation is largely unclear but is not believed to rely on the assembly of vesicle coats like those observed in other secretory pathways. The required cytosolic factors are now beginning to be identified using in vitro systems with purified cellular components. ISG transformation into a mature fusion-competent, stimulus-dependent DCG occurs as endoproteolytic processing of many DCG proteins causes continued condensation of the lumenal contents. At the same time, proteins that fail to be incorporated into the condensing core are removed by a coat-mediated budding mechanism, which also serves to remove excess membrane and membrane proteins from the maturing vesicle. This chapter will summarize the work leading to our current view of granule synthesis, and will discuss questions that need to be addressed in order to gain a more complete understanding of the pathway.