Among the caspases that cause regulated cell death, a unique function for caspase-7 has remained elusive. Caspase-3 performs 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 reasons¹. Caspases can also trigger cell-type-specific death responses; for example, caspase-1 causes the extrusion of intestinal epithelial cell (IECs) in response to infection with 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. Mechanistically, caspase-7 counteracts gasdermin D pores and preserves cell integrity by cleaving and activating acid sphingomyelinase (ASM), which thereby generates 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 is a death facilitator that delays pore-driven lysis so that more-specialized processes, such as extrusion or apoptosis, can be completed before cell death. Cells must put their affairs in order before they die.

在引起调节性细胞死亡的 caspase 中，caspase-7 的独特功能仍然难以捉摸。Caspase-3 执行细胞凋亡，而 caspase-7 通常被认为是低效的备份。Caspase-1激活gasdermin D孔来裂解细胞；然而，caspase-1 也会出于未知原因激活 caspase-7 ¹。Caspases 还可以触发细胞类型特异性的死亡反应；例如，caspase-1 会导致肠上皮细胞 (IEC) 挤出，以响应肠道沙门氏菌亚种的感染。鼠伤寒肠血清型( S. Typhimurium) ^2,3。在这里，我们在类器官和小鼠中显示，caspase-7 缺陷的 IEC 无法完成挤出。从机制上讲，Caspase-7 通过裂解和激活酸性鞘磷脂酶 (ASM) 抵消 Gasdermin D 孔并保持细胞完整性，从而产生大量神经酰胺以增强膜修复。这为完成 IEC 挤出过程提供了时间。同时，我们还表明需要 caspase-7 和 ASM 裂解来清除紫色色杆菌和单核细胞增生李斯特氏菌穿孔素孔介导的自然杀伤细胞或细胞毒性 T 淋巴细胞攻击后，通常会导致受感染肝细胞凋亡。因此，caspase-7不是传统的刽子手，而是一种死亡促进剂，可以延迟孔驱动的裂解，以便在细胞死亡之前完成更专门的过程，例如挤出或细胞凋亡。细胞在死亡之前必须把自己的事务整理好。