The role of glycosphingolipids in modulating membrane protein trafficking (360G-Wellcome-219447_Z_19_Z)

Glycosphingolipids (GSLs) are specialised lipids enriched in the outer leaflet of the plasma membrane (PM) and defects in GSL metabolism underlie a range of devastating diseases. I have shown for the first time a direct link between GSL metabolic defects and changes in the abundance of disease-associated PM proteins. Changes to the cell surface abundance of these proteins are driven by trafficking defects and gene expression changes: pathways that may be mechanistically linked. My preliminary work highlights that the role of GSLs in membrane trafficking has been under-appreciated. I now seek to define the molecular mechanisms that link GSL abundance to disease pathways: how do specific GSL-protein interactions direct membrane trafficking; and what are the consequences of this mistrafficking? We will target specific enzymes in GSL metabolic pathways, monitor lipid and protein changes using quantitative mass spectrometry and visualise co-ordinated protein trafficking from the endoplasmic reticulum using an innovative fluorescence-based secretory assay. Using high-resolution structural techniques we will determine how the specificity of GSL-protein interactions is defined and exploit these insights to feedback into our cell-based assays. My research proposal implements a multidisciplinary strategy that will reveal crucial new insights into how this important class of lipids influence cell fate.