Among caspases that cause regulated cell death, a unique function for caspase-7 has remained elusive. Caspase-3 performs apoptosis, while caspase-7 is generally considered an ineffective fallback. Caspase-1 activates gasdermin D pores to lyse the cell; however, caspase-1 also activates caspase-7 for unknown reasons1.
Caspases can also trigger cell type-specific death responses; for example, caspase-1 causes extrusion of intestinal epithelial cells (IEC) in response to infection by Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium)2,3. Here, we show in both organoids and mice that caspase-7-deficient IECs do not complete extrusion.
Mechanically, caspase-7 neutralizes gasdermin D pores and preserves cellular integrity by cleaving and activating acid sphingomyelinase (ASM), which thereby generates large amounts of ceramide to enable enhanced membrane repair. This gives time to complete the IEC extrusion process.
In parallel, we also show that caspase-7 and ASM cleavage is required to eliminate Chromobacterium violaceum and Listeria monocytogenes after perforin pore-mediated attack by natural killer cells or cytotoxic T cells, which which normally causes apoptosis of infected hepatocytes. Therefore, caspase-7 is not a conventional executioner, but rather a death facilitator that delays pore-induced lysis so that more specialized processes, such as extrusion or apoptosis, can be completed before cell death. Cells must get their house in order before they die.