Sorting out secretion

Proteins that are destined to be secreted from a cell undergo a multistep sorting and transport process, but until recently a critical portion of the secretory pathway—the transport of cargo from the Golgi apparatus—has been difficult to dissect. On page 271, Harsay and Schekman show that one population of yeast secretory proteins apparently takes a detour through an endosomal compartment on its way from the Golgi apparatus to the cell surface. Although some types of mammalian cells appear to use a secretory pathway involving endosomes, the new work is the first demonstration of such a system in yeast, a model system that should help define additional steps in this poorly understood process.

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. ▪