The long-term goal of this research program is to delineate the molecular mechanisms that regulate homeostasis of the endoplasmic reticulum (ER) in B-lymphocytes. The ER is a specialized compartment for the maturation of membrane and secreted proteins. As such, the ER is the site where immunoglobulin chains fold and assemble into functional antibodies. When B-lymphocytes differentiate into antibody-secreting plasma cells, the ER expands and adapts to accommodate high-rate antibody production. Therefore, the mechanisms that regulate ER homeostasis in differentiating B cells are critical for antibody-mediated immunity. An intracellular signaling pathway, termed the unfolded protein response (UPR), monitors the status of protein folding in the ER and transmits that information to mechanisms that modulate the ER environment. A key UPR transcriptional activator, XBP1(S), is required for plasma cell development. ER expansion includes increased expression of many ER resident proteins and elevated synthesis of phospholipids necessary for membrane biosynthesis. Both of these events have been linked to XBP1(S). This project focuses on four specific aims. First, the protein and lipid composition of the ER will be characterized in differentiating B cells and in a fibroblast model in which ER expansion is induced by enforced expression of XBP1(S). Second, the ability of the expanded ER to support protein biosynthesis will be evaluated in these systems. Third, the mechanism by which phospholipid biosynthesis increases during ER expansion will be investigated. Finally, factors that regulate ER biogenesis will be identified using biochemical and genetic approaches. These studies will yield new information concerning UPR-regulated events that control plasma cell development, generate efficient antibody responses, and mediate ER homeostasis. Importantly, the UPR has been linked to a number of physiologically significant processes including pancreatic function, skeletal development, oxidative stress, and macrophage apoptosis in atherosclerotic lesions. In addition, a number of catastrophic disorders including lysosomal storage diseases, cystic fibrosis, and Alzheimer disease have been linked to protein maturation errors in the ER. A mechanistic understanding of ER homeostasis might lead to the development of novel therapeutics for these diseases.
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