Coordination of membrane traffic in the early secretory pathway

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Proteins and lipids are the major building blocks of cells, and as such are constantly produced within the cells or our body. The constant synthesis of these molecules is required for the growth and healthy maintenance of our tissues. Approximately one third of all proteins and practically all lipids are made in a cell compartment called the endoplasmic reticulum, from where most proteins and lipids are further transported to downstream compartments in specialized carriers called transport vesicles. This transport occurs along the secretory pathway, which delivers the proteins and many of the lipids to their final destination in the cell, or in some cases the molecules are released from the cell by secretion, as is the case for hormones, neurotransmitters, extracellular proteins that make up our skin and bone, and cholesterol-rich particles that circulate in our bloodstream. A major gatekeeping step in the secretory pathway is the exit of cargo proteins and lipids from the endoplasmic reticulum, a process mediated by specialized machinery called COPII, which acts together with accessory factors to ensure cargo is released in an efficient and properly controlled manner into carriers destined for the next compartment of the secretory pathway. This forward transport of cargo must also be balanced with transport in the reverse direction, which acts to recycle key factors and is mediated by a different machinery, called COPI. The mechanisms by which forward and backward transport are coordinated, which is vital for secretory pathway function, are unknown. Moreover, although we know defective secretory cargo transport negatively impacts upon cell viability and human health, the underlying mechanisms remain poorly defined. This proposal focuses on a protein called Scyl1, whose mutation causes CALFAN syndrome in humans, a disorder that affects the nervous system, liver and skeleton. Presently we have only a poor understanding of Scyll1 function. We have obtained preliminary evidence that Scyl1 functions in conjunction with COPII, and that loss of Scyl1 disrupts cargo protein transport in the secretory pathway. These results point to a new role for Scyl1 in controlling exit of cargo proteins from the endoplasmic reticulum. Moreover, since Scyl1 is unique in its ability to bind to both COPII and COPI, it is a prime candidate for a factor coordinating forward and backward transport in the secretory pathway. Finally, because our preliminary results indicate that defective secretory cargo transport upon loss of Scyl1 causes induction of cell stress, investigating the underlying mechanisms of stress induction and its consequences will reveal how defective trafficking causes loss of cell viability, which is important for our understanding of human health. The work will not only be important for determining the mechanisms of CALFAN syndrome, but will have significance for our understanding of secretory cargo transport more generally, which is of fundamental importance to all cells.