Regulation of Cell Phospholipid Metabolism by Phospholipase A2

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Group VIA phospholipase A2 (iPLA2) is an enzyme that breaks down the lipids that comprise the membranes of mammalian cells. The enzyme has several important roles in cell biology, including regulating the amount of lipid available to make cell membranes, controlling the types of lipids in cell membranes, and regulating the production of biologically active lipids that allow cells to respond to changes in their environments. Recent evidence suggests that iPLA2 may also control the synthesis of cholesterol and the development of adipocytes (fat cells). These observations suggest that the effects of the enzyme are global and have impacts beyond the lipid metabolism of single cells. However, at present very little is known about the molecular mechanisms that control iPLA2 activity. The goal of this project is to delineate mechanisms controlling iPLA2 activity in mammalian cells. This project focuses on two mechanisms that control iPLA2 activity: alternative splicing and oligomerization. Alternative splicing refers to the concept that cells can generate different forms of iPLA2 that are active or inactive. Preliminary studies indicate that active iPLA2 enzymes may generate products that trigger the production of inactive forms of the enzyme that reduce activity. This may be an important feedback mechanism to control lipid metabolism in mammalian cells. Several iPLA2 proteins (monomers) must come together to form an active enzyme complex. Another aspect of this project is to determine how short (truncated) forms of iPLA2 prevent formation of active iPLA2 complexes and thereby suppress enzyme activity. Together, these studies will expand our knowledge of an essential homeostatic enzyme in cell lipid metabolism. The broader impact of this research is reflected in its potential to train the next generation of scientists and generate crucial knowledge concerning iPLA2 regulation and its influence on cellular and global lipid metabolism. Graduate students are directly involved in this research and have used experiments focused on the regulation of iPLA2 expression and/ or activity for their dissertation research. In addition, the project provides undergraduate students with technical training and insights into research as a career option. It also serves as a springboard for several outreach activities that are primarily focused on students at neighboring minority serving institutions (Virginia Union University, Virginia State University, and Hampton University). A more global impact of this project is its facilitation of the role of the Project Director as coordinator and participant in a seminar program that brings Virginia Commonwealth University researchers to the campuses of minority serving institutions. The overall goal of these activities is to contribute to the development of a pool of well-trained scientists and to ensure that the diversity of this pool reflects the public that it serves.