Elucidating the pathways and machinery of constitutive secretion

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The human body is made up from billions of cells and each of these cells is further organised into a series of compartments. Cells in some ways resemble miniature cities and these compartments are just like factories that make specific products, for example the endoplasmic reticulum is involved in making proteins and lipids. Once a protein or lipid has been made, its function is often required somewhere else within the cell. To transport these proteins and lipids to the site where they are needed, small packages (vesicles) break off from one compartment and fuse with another, thereby delivering their contents. These vesicles are just like lorries taking goods to different destinations within the city. In some cases the newly made proteins are required outside the cell so the vesicles carrying these proteins fuse with the membrane that covers the cell surface (plasma membrane). This process is called constitutive secretion and is required for many important processes such as inflammation and immune system function. Changes in secretion can cause disease and there is an increasing number of rare genetic disorders cause by mutations in proteins required for secretion. My laboratory is interested in identifying and characterising proteins required for generating, transporting and fusing secretory vesicles with the plasma membrane. To identify this machinery we have developed new ways of measuring secretion and used them with technologies that allow the function of individual genes to be disrupted. Using this approach we have identified two proteins, STX19 and SNAP29, that are required for secretion. This proposal aims to characterise the function of these proteins, in particular we are interested in understanding how SNAP29 and STX19 are regulated and how these proteins are targeted to the correct place within the cell. We are also interested in determining whether SNAP29 and STX19 are involved in the secretion of all types of proteins from cells or just a specific subset.This work will benefit society because it will increase our understanding of a fundamental cellular process and in the future may help in the development of new diagnostics or therapeutics for the treatment of diseases caused by defective secretion. In particular, our work should help in understanding the pathologies which occur in the rare fatal disease CEDNIK (CErebral Dysgenesis, Neuropathy, Ichthyosis, and Keratoderma) syndrome which is caused by the loss of SNAP29.