Eukaryotic cells are compartmentalised into a complex array of membrane-bound organelles. The exchange of contents between organelles is tightly regulated, and mostly relies on vesicular or tubular transport intermediates. The selectivity of transport is mediated by cytosolic coat proteins, which assemble on the donor compartment to recruit transmembrane cargo proteins into the nascent vesicle; the coat also functions as a structural scaffold required for membrane deformation and vesicle budding. Every pathway utilises a unique transport intermediate to ensure specificity. Membrane trafficking is critical for cellular survival; deletions of key components, such as major coat proteins, are embryonic lethal. Furthermore, a growing number of human genetic disorders are associated with defects in trafficking machinery, including for example congenital intellectual disability and progressive spasticity. Trafficking is also an essential part of metabolic homeostasis; conversely, many pathogens highjack trafficking pathways to evade host immunity. A complete understanding of membrane trafficking will benefit many areas of cell and clinical biology.
The dynamic interconnectedness of all transport steps poses a big challenge in the analysis of trafficking phenomena. Experimental interference with one pathway likely affects other pathways, resulting in indirect effects and complex phenotypes. A related question is the overall regulation and co-ordination of trafficking events, a central yet largely unexplored aspect of cellular organisation. Our group develops proteomics based systems biology approaches for characterizing post-Golgi trafficking pathways. A particular focus of our research is the AP-4 pathway, and the mechanism by which loss of AP-4 function causes hereditary spastic paraplegia.
Dr. Daniel Itzhak, post doc