Controlling caspase activity in life and death

Every day, billions of human cells terminate their normal activities and launch intrinsic suicide pathways. Timely cell death is orchestrated by destructive functions encoded by dying cells, such as caspase proteases in the case of apoptotic or pyroptotic cell death. Caspases cleave specific intracellular substrates to kill and dismantle cells destined for elimination, and their dysregulation leads to a range of human disorders [1]. Drosophila models have proven to be key tools for understanding the regulation of caspases in cell death, but have also revealed other unanticipated roles for caspases, including cell proliferation [2], sperm maturation [3] and neuronal pruning [4]. Furthermore, the presence of widespread, nonlethal caspase activity in fly tissues suggests that there could be additional caspase-dependent processes besides those that are already known [5]. Thus, a new challenge is to understand the connections between non-death and pro-death functions of caspases. A new study from the Bergmann lab [6] reveals that mono-ubiquitylation of the Drosophila caspase Dronc inhibits apoptosis; more surprisingly, mono-ubiquitylation also inhibits an alternative role of Dronc. This work uncovered a role for Dronc in several non-lethal activities and organismal survival that apparently does not require Dronc's protease activity.