Completed Cells, Biochemistry & Physiology Diabetes, Hormones & Metabolism

The role of glycosphingolipids in modulating membrane protein trafficking

Funder Wellcome Charity-funded
Recipient organisation University of Cambridge
Funding £1.9M
Period Apr 2020 — Apr 2025

In plain English

AI plain-English summary

Every cell in the human body uses fatty molecules called glycosphingolipids to control which proteins sit on its surface, and when that system breaks down, it can trigger devastating diseases. These lipids are concentrated in the outer layer of the cell membrane, and defects in how the body makes or breaks them down are linked to conditions like lysosomal storage disorders. The researcher has already shown that these metabolic defects directly change the number of key proteins on the cell surface, but the underlying mechanism is unknown. This project aims to uncover exactly how specific glycosphingolipids grab hold of proteins and direct their movement through the cell, from the endoplasmic reticulum to the plasma membrane. This is fundamental science. There is no immediate clinical application. The team will use mass spectrometry to track lipid and protein changes, a fluorescent assay to watch protein trafficking in real time, and high-resolution structural techniques to map the molecular handshake between lipid and protein. If successful, the work will reveal a new layer of cellular control—how a class of lipids that has been largely overlooked influences which proteins a cell displays, and therefore how it communicates with its environment. That knowledge could eventually point toward new targets for treating diseases rooted in lipid metabolism.

View original technical description
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.

View the original record at the funder ↗

Researchers

Janet Deane (EPMC Awardee)

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Original classification

Senior Research Fellowship

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