Selective packaging of proteins for secretion via COPII vesicles

ongoing

Protein secretion is an essential cellular process that delivers many diverse proteins to the extracellular environment or cell surface. This process contributes to many aspects of cellular function, including nutrient uptake, cellular communication and tissue integrity. Secretion starts with secretory protein biogenesis and folding in the endoplasmic reticulum (ER) followed by their export from the ER and transport to the Golgi apparatus via COPII-coated vesicles, to finally reach their final destinations. These vesicles play a pivotal role in quality control of secretion by selectively packaging cargo proteins that are fully folded and transport competent. Defects in this process can lead to diseases such as cancer and neurodegenerative disorders. However, the molecular mechanisms governing selectivity in vesicular trafficking remain poorly understood. PACK-COP will reveal how a specific family of cargo receptors, Erv14/CNIH, drives the selectivity of secretion across a diverse range of clients. The molecular mechanism underlying this selectivity into nascent vesicles will be dissected using a combination of yeast and human model systems. In yeast, PACK-COP will use mutagenesis and specific cross-linking approaches to discover protein-protein interaction interfaces that drive multiple known cargo proteins into COPII vesicles. These insights will be directly applied to human cells to map the client landscape that uses CNIH1 for ER export, and test specific functional domains based on the yeast discoveries. The innovative combination of both models, coupled with cutting-edge techniques, will enable PACK-COP to map Erv14 specific amino acids required for the ER export of critical cell-surface proteins. This knowledge could enable screening for inhibitors that block these interactions, potentially reducing the release of specific proteins to the cell surface, a strategy with significant therapeutic potential for disease associated to defects in secretion pathways.