The balance between cell death and survival is essential for animal development and tissue homeostasis. While most cell death occurs by caspase-mediated apoptosis, other cell death modalities including autophagy-dependent cell death play key spatiotemporally restricted roles. Originally identified for its role in cell survival, autophagy is the catabolic process that engulfs cytoplasmic material in an autophagosome prior to fusion with the lysosome. Lysosomes are acidic organelles containing hydrolytic enzymes including cathepsin proteases that degrade and recycle cellular components. Autophagosome-lysosome fusion is required for autophagic flux, yet the contribution of the lysosome to autophagy-dependent cell death remains to be established.
We use Drosophila to study hormone-regulated modes of cell death, including the degradation of larval midgut during metamorphosis. Our studies have shown that midgut degradation is dependent upon autophagy but does not depend on apoptosis [1]. We have also shown that multiple signals including ecdysone and growth signals are important for the temporal induction of autophagy-dependent cell death [2,3]. Furthermore, our findings revealed that only a subset of the multi-subunit complexes required for autophagy during cell survival are essential for autophagy-dependent cell death [4]. This suggests that there are yet to be identified novel regulatory proteins and mechanisms required for autophagy-dependent cell death. We have used proteomic and genetic approaches to identify tissue specific regulators of autophagy-dependent cell death. These have identified genes involved in autophagosome-lysosome formation and lysosomal proteins, cathepsins. In our ongoing studies we found that cathepsin-deficient midgut cells have increased autophagy puncta, suggesting an accumulation of autophagosomes/autolysosomes. The findings from these studies will be presented.