Mechanism and function of organization of secretory cargo export from the endoplasmic reticulum.

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The internal organization of mammalian cells has been well documented since the dawn of cellular microscopy. It is therefore quite astonishing how little we know about why the cell is laid out in this way - in simple terms, how does form dictate function? A great example of this comes from the organization of the secretory pathway. All proteins secreted from your cells go through this pathway - all hormones (insulin, growth factors, digestive enzymes), all neurotransmitters, all antibodies made by your immune cells. Furthermore, all of the proteins that sit on the surface of your cells to recognize these key signalling molecules are put there by the secretory pathway. Indeed, all internal cell membranes are composed of proteins that are targeted to these individual compartments by the secretory pathway and serve to define the identity of the membranes where they reside. Why then is the first step of the secretory pathway organized at discrete sites known as transitional ER (tER). These spots that can be seen in the cell when labelled with specific markers are the first site of spatial organization of the secretory pathway. As such, in the same way that the foundations define the architecture of a building, these sites define the architecture of the cell. We and our new collaborators have identified two of the proteins that define these tER sites and now wish to go on to show how these act together to generate these sites and how their interdependent function relates to the core organization of the tER. Following on from some of our preliminary data, we are now in a position to ask the fundamental question of how tER organization directs function. We have evidence that we can disrupt organization without blocking core activity. We propose to investigate the role of this organization in the core activities of the secretory pathway and in particular focus on the role of tER organization in the secretion of the most abundant protein in your body, collagen. We have good evidence that these core proteins play a key role here and some evidence that they might even be involved directly in processing collagen during its synthesis. Funding this project will enable us to make major contributions to our fundamental understanding of cellular organization and function. Such findings have good potential for relevance to those seeking to study the dysfunction of this pathway in disease as well as those seeking to manipulate it for therapeutic benefit (the production of clinically active secreted molecules, modifying the secretory load of cells etc).