Dissecting the roles of ZFPL1 and GMAP210 in Golgi biogenesis and membrane traffic

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All cells from animals, plants and fungi are made up of different compartments, each with a unique composition and specific functions. Material is transported between these compartments, or organelles, in membrane-bound packets called vesicles. This process, referred to as membrane traffic, is required for the correct functioning of cells, and organisms as a whole. For example hormones, antibodies, neurotransmitters, and the major components of skin, cartilage and bone are released from cells in vesicles that fuse with the cell surface, while growth factors and dead cells are removed from the bloodstream in vesicles that are taken up from the cell surface. One of the major compartments in cells is the Golgi apparatus, a collection of flattened membrane sacks called cisternae that are layered on top of each other to form stacks. The Golgi apparatus has two major functions: it is responsible for modifying sugar chains present on proteins and lipids; and the packaging of these molecules into transport vesicles for delivery to the cell surface or other compartments in the cell. Proper modification and delivery of proteins is of fundamental importance. Defects in Golgi function, and membrane traffic in general, are responsible for a number of human diseases. Furthermore, components of the membrane traffic machinery, including those at the Golgi apparatus, are hijacked by certain bacteria and viruses, allowing these pathogens to replicate and/or avoid detection by the immune system. It is therefore important we understand how the Golgi apparatus functions at the molecular level. All membrane traffic steps involve a process called tethering, which is the initial attachment of the transport carrier to its destination compartment. There are many tethering factors in cells, including a family of related tethering proteins at the Golgi apparatus. Mutation of one of these proteins called GMAP210 has recently been shown to cause a lethal skeletal disease in humans. The mechanisms by which occurs are poorly understood, as are the details of how GMAP210 and other tethering factors work in healthy cells. The aim of this proposal is to determine how GMAP210 function is regulated, focussing on its association with another protein of the Golgi apparatus that we have recently identified. This work will inform us of how the fundamental process of tethering takes place inside cells, and how defects in this process can lead to skeletal and possibly other types of disease in humans.