Abstract/Project Summary Defects in autophagy, the self-degradation of cellular components, are linked to multiple disorders such as cancer, diabetes and neurodegenerative diseases. Autophagosomes, containing cargo marked for degradation, fuse with lysosomes to recycle cell resources, such as protein aggregates and damaged organelles. However, we know little about the mechanisms that regulate the association between autophagic cargoes and autophagosome formation. Here, I investigate the role of vps13d, an essential gene with relatively unknown function, in context-specific autophagy and cell death in the developing Drosophila intestine. Proteins that regulate autophagy and cell death are of particular interest given the roles they play in tumorigenesis. Previous studies of VPS13D identified a role in the clearance of mitochondria by autophagy, also known as mitophagy. Intriguingly, VPS13D also appears to be involved in dissolution of membrane contacts that are associated with autophagosome formation. Furthermore, little is known about the role of VPS13D in associating autophagy-bound cargo with the site of autophagosome formation, despite having links to the core autophagy machinery. I hypothesize that VPS13D facilitates context-dependent autophagy by associating ubiquitinated cargo with the autophagic machinery and disassembling membrane contact sites at the phagosome assembly site (PAS). Here I propose to determine if VPS13D functions as an autophagy receptor for ubiquitinated cargo and determine the relationship between VPS13D and membrane contact modulator Vacuole Membrane Protein 1 (VMP1). The association of VPS13D and mutations in other factors that regulate autophagic cargo recruitment with human disorders illustrates the importance of studying VPS13D function.

Project Narrative Autophagy plays an important role in animal health and development, and defects in this process are associated with a variety of human disorders including neurodegeneration, cancer and inflammatory diseases. I am investigating novel mechanisms that control cell context-specific regulation of autophagy during animal development. The recent association of autophagy with multiple diseases, and interest in manipulating autophagy for therapeutic purposes, illustrates the importance of investigating the mechanisms that control cell context-specific regulation of autophagy.