Among the caspases that cause regulated cell death, a unique function for caspase-7 remained elusive. Caspase-3 executes apoptosis, whereas caspase-7 is typically considered an inefficient back-up. Caspase-1 activates gasdermin D pores to lyse the cell, however, caspase-1 also activates caspase-7 for unknown reasons(1). Caspases can also trigger cell-type specific death responses, for example caspase-1 causes intestinal epithelial cell (IEC) extrusion in response to Salmonella Typhimurium infection(2,3). Here we show in both organoids and mice that caspase-7-deficient IECs fail to complete extrusion. Mechanistically, caspase-7 counteracts gasdermin D pores and preserves cell integrity by cleaving and activating acid sphingomyelinase (ASM), thereby generating copious amounts of ceramide to enable enhanced membrane repair. This provides time to complete the process of IEC extrusion. In parallel, we also show that caspase-7 and ASM cleavage are required to clear Chromobacterium violaceum and Listeria monocytogenes after perforin pore-mediated attack by natural killer cells or cytotoxic T lymphocytes; which normally causes apoptosis in infected hepatocytes. Therefore, caspase-7 is not a conventional executioner, but instead, a death facilitator that delays pore-driven lysis so that more elegant processes, such as extrusion or apoptosis, can be completed prior to cell death. Cells must put their affairs in order before they die.
