Autophagy and programmed cell death (PCD) are essential for animal development and for the maintenance of cell and tissue homeostasis. Autophagy is a conserved process that delivers components of the cytoplasm to lysosomes for degradation. Most PCD occurs by caspase-mediated apoptosis, with other mechanisms such as autophagy-dependent cell death, having crucial spatiotemporal restricted roles.
Drosophila is a powerful model to study hormone-regulated modes of programmed cell death (PCD) during development. During the late third instar larval stage, a large ecdysone pulse triggers the PCD of the obsolete larval tissues, including the larval midgut. In our seminal findings we discovered that autophagy acts as a cell death mechanism required for the removal of the larval midgut. Midgut PCD occurred normally in the absence of the apoptotic machinery, where as inhibition of autophagy blocked degradation. We found that hormonal cues together with growth arrest are prerequisite for autophagy-dependent midgut PCD.
As autophagy can act as either a cell survival or cell death mediator this raises the question of how autophagy specifically results in the demise of the cell. Our recent studies have shown that some components of the canonical autophagy pathway required for survival are dispensable for autophagy-dependent cell death. This suggests that autophagy-dependent cell death may involve distinct and novel regulatory proteins and mechanisms. We have been using proteomic and genetic approaches to identify tissue specific regulators of cell death verses cell survival autophagy. In further studies examining signalling pathways that regulate autophagy-dependent cell death we have now identified an unexpected role for the TGF-β homologue, Decapentaplegic (Dpp), as a key player in this process. The findings from these studies will be discussed.