Larval midgut destruction in Drosophila: not dependent on caspases but suppressed by the loss of autophagy

Abstract

While most programmed cell death (PCD) in animal development is reliant upon the caspase-dependent apoptotic pathway and subsequent cleavage of caspase substrates, we found that PCD in Drosophila larval midgut occurs normally in the absence of the main components of the apoptotic machinery. However, when some of the components of the autophagic machinery were disrupted, midgut destruction was severely delayed. These studies demonstrate that Drosophila midgut PCD is executed by a novel mechanism where caspases are apparently dispensable, but that requires autophagy.

Figure 1

Most developmental cell death in Drosophila is mediated by the canonical caspase activation pathway involving the initiator caspase Dronc and the effector caspase Drice. Drice function can be compensated by a similar caspase Dcp-1 (not shown here) in drice mutant animals. The Drosophila inhibitor of apoptosis protein (Diap1) prevents Dronc activation, whereas Ark, an adaptor that forms a Dronc-activation scaffold often called `apoptosome,' promotes Dronc activation. As discussed in this `punctum,' in Drosophila larval midgut, the Dronc-Ark-Drice/Dcp-1 pathway is dispensable for PCD. It appears that in the absence of this pathway, a noncanonical cell death mechanism involving autophagy mediates PCD, although how autophagy mediates midgut PCD is currently unknown. In the midgut, activation of the caspase Decay can occur without the Dronc-Ark-Drice/Dcp-1 pathway, suggesting an alternative mechanism(s) of caspase activation. However, the role of Decay in midgut cell death, if any, is unclear, as its inhibition/depletion has no effect on midgut PCD.