On page 455, Inbal et al. describe some of the first molecules directly linked to the control of autophagic cell death. They suggest that these proteins may constitute a link between the ancient process of autophagic cell death and the more recent phenomenon of apoptosis.
The proteins in question are DAP kinase (DAPk) and DRP-1, two closely related, death-promoting, Ca2+/calmodulin-regulated kinases. Inhibiting DAPk slows death caused by many different stimuli, and the kinase is known to act as a tumor suppressor, probably by inducing cell death.
Inbal et al. find that dominant–negative versions of the kinases have two significant effects. They inhibit blebbing in apoptotic cells (although DNA condensation and fragmentation continue) and largely block the autophagic cell death normally caused by amino acid starvation or steroid withdrawal.
Constitutively active versions of the kinases induce, independently of caspase activity, both membrane blebbing and autophagic vacuole formation. In these specific settings, the mutant kinases do not trigger other phenotypes of apoptosis, such as mitochondrial disruption, and cell and DNA fragmentation.Both wild-type kinases can phosphorylate myosin light chain, which may induce cortical contractions leading to blebbing. But the connection between this possible mechanism and autophagy remains unclear. Perhaps evolution has retained the same molecules for both forms of cell death, but used them in two different ways. ▪