A major aim of our work is to understand how cells regulate the delivery of proteins to their surface. In eukaryotic cells, secreted and cell surface proteins are transported from the site of synthesis in the endoplasmic reticulum (ER), through a series of intracellular compartments (ex: ERGIC, the Golgi, endosomes) to the cell surface. The correct trafficking of digestive enzymes, neurotransmitters, hormones, morphogens, signal transducing molecules, adhesion proteins, etc is responsible for all human developmental and life processes. My laboratory is developing a "virtual" time and space map of all of the molecular events that regulate trafficking. We were the first to clone several proteins that are required for transport and are now using biochemical, morphological, molecular and genetic methods to define their exact functions. We concentrate on two large families of proteins: 1) tethering factors that appear to link membranes prior to fusion and 2) proteins with guanine nucleotide exchange activity that promote cargo selection during transport. The tethering proteins appear to act as molecular "Velcro" to facilitate correct membrane-membrane pairing before fusion. The exchange factors act as molecular "fly paper" that selects and keeps a patch of cargo for incorporation into a transport vesicle. 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.
A complementary area of focus within our group is the control of ciliogenesis. Cilia have emerged as key organelles that control development and sensory processes. These small projections of the cell surface sense and relay external information to the cell, acting like an antenna that tells the cell what is happening in its immediate environment. Defects in cilia assembly or in specific ciliary proteins cause severe human diseases that include obesity, hypertension, cystic kidneys, skeletal defects, blindness, anosmia, and infertility. Cilia must contain a full complement of sensory proteins to facilitate correct signaling. We study how newly synthesized ciliary proteins are trafficked to cilia. Once deployed to the cilia, the residence time of ciliary sensors must be tightly regulated as to fine-tune the reception. We are investigating how ciliary proteins are removed from cilia and then re-deployed to once again sense the environment. Our work will uncover the mechanisms by which ciliary function is regulated. Such knowledge will identify novel therapeutic targets for intervention into human ciliopathies.
In addition, we are involved in a project exploring protein degradation. Chaperones catalyze the correct folding of newly synthesized proteins in the ER. Incorrect or inefficient folding leads to the scavenging of the protein by the ER quality control system and its elimination by proteasomal degradation. We have developed an in vivo system, using the genetically tractable yeast, S. cerevisiae, to analyze the process. This allowed the identification of a multi-component sorting machinery in yeast that sequesters misfolded proteins in ER subdomains prior to their degradation. We are seeking to identify a similar system in mammalian cells. In addition, we are exploring the relationship between proteasomal degradation and a separate degradative pathway, autophagy. We have uncovered that overtaxing the proteasomal pathway by overloading the cell with misfolded proteins or by stress leads to upregulation of autophagic degradation. We are now investigating the molecular signaling that links the two pathways. the goal of this project is to develop target-based technology that will selectively slow the degradation of clinically relevant proteins.
Elizabeth S. Sztul obtained a M.Sc. (1979) in Plant Physiology from University of Maryland, studying chloroplast biogenesis. She continued her graduate studies in Cell Biology at Yale University School of Medicine, working on membrane trafficking pathways in the laboratory of Nobel Prize winner, Dr. George Palade, and was awarded a Ph.D in 1984. She continued training as a Postdoctoral Fellow of the American Cancer Society (1985-1989) in Human Genetics at Yale University School of Medicine, working on mitochondrial biogenesis in the laboratory of Dr. Leon Rosenberg. During her postdoctoral work at Yale, she was also a Visiting Scientist at the European Molecular Biology Laboratory in Heidelberg, Germany, in the laboratory of Dr. Kathryn Howell. She was appointed Assistant Professor of Molecular Biology at Princeton University (1989-1995), where she received the National Science Foundation Presidential Young Investigator Award. Dr. Sztul joined the faculty in the Department of Cell Biology at UAB as an Associate Professor in Fall of 1995. She is a member of the UAB Comprehensive Cancer Center and of the Fleming Cystic Fibrosis Center. She spent a sabbatical year (2000-01) at the Wellcome Center for Human Genetics in Oxford, United Kingdom, in the laboratory of Dr. Yvonne Jones. At the national level she has served or serves on Scientific Advisory Panels for the National Institute of Health, American Cancer Society, National Science Foundation and the American Heart Association.