Previous work demonstrated that yeast sec6 mutants exhibit a post-Golgi secretion defect that causes the accumulation of two populations of secretory vesicles, distinguished by their differing buoyant densities and cargos. In this genetic background, Harsay and Schekman found that mutations in VPS genes, affecting transport to an endosomal compartment, also block protein sorting to the high-density secretory vesicles. In these double mutants, proteins normally targeted to the high-density vesicles are instead sorted into the light-density vesicles.
This is the first time newly synthesized soluble exocytic proteins have been shown to move through an endosomal compartment on the way to being secreted. While it is still unclear why the cell would have two separate secretion pathways, one possibility is that the less abundant high-density vesicles, which are enriched in enzymes for particular metabolic processes, may allow rapid responses to environmental changes without causing membrane expansion.The cell's ability to reroute secretory proteins from one pathway to another may also explain why it has been difficult to isolate mutants defective in the post-Golgi portion of the secretion process: both pathways would have to be shut down simultaneously to block secretion. Using mutations that block the high-density vesicle pathway, the authors are now trying to identify genes involved in the light-density vesicle pathway. ▪