Regulation of autophagy during animal development

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ABSTRACT Autophagy is used by all cells to deliver cytoplasmic material to the lysosome for degradation. Significantly, autophagy has been implicated in several human diseases, including inflammatory disorders, cancer and neurodegeneration. Most of what we know about the regulation of autophagy is based on pioneering studies in yeast that defined the core autophagy machinery, but recent studies in animals have revealed that autophagy can possess different regulatory mechanisms in distinct cell types. Our research program aims to understand how autophagy is regulated in 2 cell types during development of Drosophila. This system possesses several advantages for these studies, including robust genetic, genomic and cell biological tools that enable sophisticated cellular analyses at single cell resolution. We have focused on studying autophagy in dying larval salivary gland cells and midgut enterocyte cells of the intestine as models. Both salivary gland and midgut cells require autophagy for proper death and degradation, but use entirely different mechanisms for the activation of autophagy. Salivary gland autophagy is regulated by an ancient inflammatory signaling pathway that includes the complement factor Mcr and the engulfment receptor Draper, but this pathway is not required for autophagy in either fatbody cells following nutrient deprivation or midgut cells of the intestine during development. By contrast, midgut cells of the intestine require a ubiquitin-dependent autophagy program that interfaces with mitochondrial dynamics through the novel Vps13D protein. Significantly, Vps13D is not required for autophagy in either fatbody or salivary gland cells. Our future research program contains 4 projects that will address key questions in the autophagy field. What is the role of inflammatory signaling in developmental autophagy? What is the role of mitochondrial dynamics in autophagy? What is the role of ubiquitin in autophagy? What is the role of previously undiscovered pathways in context-specific regulation of autophagy? These proposed studies will address a critical gap in our knowledge about the cell context-specific mechanisms that regulate autophagy within an animal. Given the strong conservation of autophagy mechanisms between Drosophila and mammals, we expect that what we discover will provide insight into the diversity of mechanisms that control autophagy in humans, and how alterations in autophagy in different cell contexts may lead to disease. Furthermore, an understanding of the diversity of mechanisms that control autophagy in animals is essential knowledge for the design of rationale strategies to target autophagy for disease therapies.