Membrane repair boosted by caspase signaling

Abstract Cells undergo several types of regulated cell death, often initiated by proteases in the caspase family. Once initiated, regulated cell death activates multiple processes in the cell in order to accomplish the demise of the cell in a regulated fashion. For example, intestinal epithelial cells undergo the process of extrusion, whereby the cell is detached from the epithelial monolayer and ejected into the lumen of the intestine. The process of extrusion takes about 10 minutes, and requires that the extruding cell actively participate in the process by disassembling its cytoskeleton, reassembling a contractile actomyosin ring, and then constricting and disassembling adhesions to neighboring cells. Thus, the cell must remain alive for about 10 minutes, and during that short time it must complete what we term a “bucket list” of tasks that accomplish the extrusion process. Similarly, cells undergoing apoptosis activate multiple cellular processes to disassemble cellular structures and package them into apoptotic blebs. This takes perhaps 30-60 minutes, the time in which the cell must complete a bucket list of apoptotic tasks. Failure to complete these bucket lists will result in a defective form of cell death that can be pathological. We recently discovered that caspase-7, once thought to be a cell death executioner, is actually a death delaying caspase that buys the cell time to complete these bucket lists. Caspase-7 hyperactivates the acid sphingomyelinase membrane repair pathway, allowing dying cells to more efficiently repair damage to their membranes. Here we study the molecular mechanisms that enable caspase-7 to accomplish this unique function.