The Drosophila proprotein processing protease is required for glucose homeostasis and developmental progression
Rhea, Jeanne Marie
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Neuropeptides are an important class of chemical messengers that allow an organism to alter behavior, development, and other physiological processes in response to a constant barrage of stimuli from both internal and external environments. Most peptide hormones are synthesized as larger, inactive precursor molecules that require proteolytic processing by one or more members of a family of subtilisin-like proprotein convertases (PCs) to generate a biologically active molecule. Differential processing due to cell specific expression of different PCs can result in production of distinct sets of active peptide hormones from the same precursor peptide. Thus, processing by PCs represents an important regulatory mechanism of peptide hormone signaling. This thesis describes a genetic dissection of prohormone processing in the model system Drosophila by amontillado (amon), the homolog of mammalian PC2. PC2 is a PC expressed in the regulated secretory pathway, and is one of the two main convertases responsible for the proteolytic activation of endocrine and neuroendocrine hormones. Here, we provide evidence that amon regulates glucose homeostasis and development in Drosophila by proteolytically activating peptide hormones involved in these processes, including the Drosophila insulin-like peptides (dilps) and adipokinetic hormone (akh) – the vertebrate glucagon analog. We have demonstrated that amon function is both necessary and sufficient in the AKH producing cells to maintain normal glucose homeostasis. amon function is also important in the insulin producing cells (IPCs) as a cell-type specific loss of amon results in hyperglycemic larvae. In addition to regulating physiological processes, we demonstrated a molting requirement for amon in a subset of cells in the CNS. Together, these studies support a regulatory role for amon in Drosophila metabolism and development. We also establish Drosophila as a useful system in which to study the cell-type specificity of prohormone processing, to identify the function of known neuropeptides, and to potentially identify novel hormone signals. Given the highly conserved nature of developmental and metabolic pathways, these studies in Drosophila have the potential to provide invaluable insight into the development of human diseases and metabolic disorders.