BBB Seminar: Elizabeth S. Sztul
Molecular regulation of membrane traffic
Elizabeth S. Sztul,
Department of Cell Biology, University of Alabama, Birmingham, USA
Our major aim is to understand how cells regulate the delivery of proteins to their surface. In eukaryotic cells, secreted and integral membrane proteins are transported from the site of synthesis in the endoplasmic reticulum (ER) through a series of intracellular compartments (e.g. ERGIC and the Golgi) to the cell surface. Correct trafficking of digestive enzymes, neurotransmitters, hormones, morphogens, signal transducing molecules, adhesion proteins etc. is responsible for all human developmental and life processes. Our laboratory is developing a “virtual” time and space map of the molecular events that regulate trafficking. We were the first to clone several transport machinery proteins and are now using biochemical, morphological, molecular and genetic methods to define their exact functions. The ultimate goal of our studies is to provide a detailed understanding of protein traffic at the molecular level as a basis for the development of disease-specific therapies that target the deficient steps in protein traffic.
Recently, we have probed how cells integrate forward and recycling traffic between the ER and the Golgi. The Golgi receives continuous membrane input from the ER, and recycling of membranes is essential to prevent the Golgi from uncontrolled expansion. By assessing how cells regulate bi-directional ER-Golgi traffic we uncovered that the tethering factor p115 functions as a coordination platform: p115 interacts with SNAREs to promote fusion of membranes with the Golgi, and also binds to the guanine nucleotide exchange factor GBF1 to nucleate the formation of COPI vesicles that recycle membranes back to the ER. Thus, p115 appears to be a master regulator that simultaneously controls forward and recycling traffic at the ER-Golgi interface.
We also have been exploring how cells control traffic through multiple compartments of the Golgi. Membranes are continuously added at the entry face of the Golgi (cis) and then consumed at its exit side (trans). Thus, we are exploring how traffic into the Golgi links with traffic out of the Golgi. We discovered that GBF1 not only regulates vesicle traffic into the Golgi (the GBF1 effect is indirect, since the protein allows forward traffic by recycling membranes to the ER for the formation of new Golgi-destined vesicles), but also the function of two guanine nucleotide exchange factors that operate in vesicle budding from the trans-Golgi. Thus, GBF1 appears to be a key regulator of membrane flow within the secretory pathway.
Host: Jaakko Saraste, Department of Biomedicine