Role and Regulation of Autophagy During Developmental Cell Death in Drosophila Melanogaster: A Dissertation

Abstract

Autophagy is a conserved catabolic process that traffics cellular components to the lysosome for degradation. Autophagy is required for cell survival during nutrient restriction, but it has also been implicated in programmed cell death. It is associated with several diseases, including cancer. Cancer is a disease characterized by aberrant cell growth and proliferation. To support this growth, the tumor cell often deregulates several metabolic processes, including autophagy. Interestingly, autophagy plays paradoxical roles in tumorigenesis. It has been shown to be both tumor suppressive through cell death mechanisms and tumor promoting through its cytoprotective properties. However, the mechanisms regulating the balance between cell death and cell survival, as well as the metabolic consequences of disrupting this balance, are still poorly understood. Autophagy functions in both cell survival and cell death during the development of Drosophila melanogaster, making it an ideal model for studying autophagy in vivo. My research aimed to better understand the regulation and metabolic contribution of autophagy during cell death in Drosophila. I found that the Ral GTPase pathway, important to oncogenesis, regulates autophagy specifically during cell death in Drosophila larval salivary glands. Contrary to previous studies in mammalian cell culture, Ral is dispensable for autophagy induced during nutrient deprivation suggesting that Ral regulates autophagy in a context-dependent manner. This is the first in vivo evidence of Ral regulating autophagy. I found that disrupting autophagy has an extensive impact on an organism’s metabolism. Additionally, I found that autophagy in degrading tissues is crucial for maintaining the fly’s metabolic homeostasis, and that it may be important for resource allocation amongst tissues. This research highlights the importance of understanding how pathways regulate autophagy in different cell contexts and the metabolic outcomes of manipulating those pathways. This is especially important as we investigate which pathways to target therapeutically in an effort to harness autophagy to promote cell death rather than cell survival.