Mechanisms of transport of the leaderless protein galectin-3 to the cell surface (360G-Wellcome-109152_Z_15_A)

Unconventional protein secretion is a poorly understood physiological process in which proteins without an N-terminal signal sequence exit the cell. There are currently four proposed pathways by which unconventionally secreted proteins are thought to exit the cell: by direct translocation across the membrane, via secretory lysosomes, by release from exosomes or multivesicular bodies, or through membrane blebbing. No complete mechanism has been described for any of these pathways, representing a significant gap in our knowledge of protein trafficking. Unconventionally secreted proteins play important extracellular roles physiologically, but abnormal levels are associated with several human diseases, including metabolic disease. As such, this mechanism is interesting to gain an insight into disease as well as to broaden our understanding of cell biology. I will investigate the unconventional transport of galectin-3 to the cell surface. Galectin-3 will here be used as a model to understand the mechanism of unconventional secretion. Data-driven and hypothesis-driven approaches will feed into each other to form a picture of how galectin-3 is secreted. A CRISPR-Cas9 screen has identified potential proteins that decrease cell surface galectin-3, providing the starting point for further investigation. Hypothesis-driven experiments will be used to investigate aspects of the models previously proposed.